The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_005609.4(PYGM):c.148C>T (p.Arg50Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(34)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
34
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005609.4(PYGM):c.148C>T (p.Arg50Ter)
Variation ID: 2298 Accession: VCV000002298.87
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.1 11: 64759751 (GRCh38) [ NCBI UCSC ] 11: 64527223 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Oct 26, 2024 Mar 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005609.4:c.148C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005600.1:p.Arg50Ter nonsense NM_001164716.1:c.148C>T NP_001158188.1:p.Arg50Ter nonsense NC_000011.10:g.64759751G>A NC_000011.9:g.64527223G>A NG_013018.1:g.5965C>T - Protein change
- R50*
- Other names
-
Arg49*
MA R49x
R49X
- Canonical SPDI
- NC_000011.10:64759750:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00100 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00109
Exome Aggregation Consortium (ExAC) 0.00137
The Genome Aggregation Database (gnomAD), exomes 0.00145
The Genome Aggregation Database (gnomAD) 0.00181
Trans-Omics for Precision Medicine (TOPMed) 0.00189
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PYGM | - | - |
GRCh38 GRCh37 |
- | - | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (20) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000002388.60 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV000081306.57 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2014 | RCV000622729.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 18, 2021 | RCV001730469.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 19, 2022 | RCV003319158.9 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 24, 2020 | RCV002251857.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 06, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511631.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000373042.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is … (more)
The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Jun 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713109.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with … (more)
The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong. (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Mar 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002107134.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product … (more)
The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2298; PMID: 20301518; PMID: 23653251; PMID: 17324573; PMID: 12929201; PMID:20301518) - PS4. The variant is present at low allele frequencies population databases (rs116987552 – gnomAD 0.01499%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg50*) was detected in trans with a pathogenic variant (PMID: 23653251; PMID: 17324573) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 2
Sex: mixed
Geographic origin: Brazil
|
|
|
Pathogenic
(Oct 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580462.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1_STR, PS3, PS4_MOD, PM3, PP1
|
Number of individuals with the variant: 2
Sex: female
|
|
|
Pathogenic
(Dec 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761410.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to … (more)
The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 50 (PVS1). The variant has been reported in probands with a clinical presentation of OMIM:232600 ( Reported multiple times in OMIM:608455 ) (PS4). Well-established functional studies show a deleterious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease ) (PS3). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Identified in another case as compound het with a second pathogenic variant in PYGM (c.613G>A;p.Gly205Ser). This variant was shown to be maternally inherited and the c.613G>A variant is paternally inherited in that case. The variant has been reported in dbSNP (rs116987552) and in the HGMD database: CM930629. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2298). (less)
|
|
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Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767308.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with McArdle disease (MIM#232600). (I) 0106 - This gene is associated with autosomal recessive disease. However, a single family has been reported for an autosomal dominant glycogen storage disorder (PMID: 32386344). (I) 0115 - Variants in this gene are known to have variable expressivity. Some affected individuals have minimal symptoms with essentially no limitations in activities of daily living. This may be attributed to variable physical activity habits (Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 253 heterozygotes, 1 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Several NMD-predicted variants have been reported in patients with McArdle disease (MIM#232600) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several McArdle disease (MIM#232600) patients in both homozygous and compound heterozygous states (ClinVar; PMID: 29143597). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001969). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Oct 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329478.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull … (more)
Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25873271, 31980526, 32124677, 31517061, 29961518, 30609409, 30316539, 30415384, 29382405, 22995991, 22344438, 20981092, 18667317, 10918252, 9120482, 27899787, 27300253, 26670295, 27031745, 22730558, 27030740, 22818872, 8316268, 17404776, 25741863, 26240973, 25240406, 25914343, 23653251) (less)
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|
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Pathogenic
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714990.2
First in ClinVar: Jun 15, 2021 Last updated: Apr 09, 2023 |
Comment:
PM2, PVS1
|
|
|
Pathogenic
(Jun 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004021025.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: PYGM c.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: PYGM c.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0015 in 251452 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease Type V, also known as McArdle disease, (0.0015 vs 0.0035), allowing no conclusion about variant significance. c.148C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type V (example: Cerino_2022). These data indicate that the variant is very likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35741838). Twenty submitters have cited clinical-significance assessments (all pathogenic) for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV004032465.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019575.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000626780.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs116987552, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503615.2
First in ClinVar: Apr 23, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result … (more)
This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result in nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. The variant is present in a large population cohort at a frequency of 0.15% (rs116987552, 424/282,854 alleles, 0 homozygotes in gnomAD v2.1), and is the most common pathogenic variant associated with glycogen storage disease type V (also known as McArdle disease) in the European population. The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in many cases with a clinical diagnosis of McArdle disease (PMID: 8316268). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong. (less)
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|
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Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247785.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PYGM: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Number of individuals with the variant: 10
|
|
|
Pathogenic
(Jan 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000590832.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Observation 1:
Age: 10-19 years
Sex: female
Comment on evidence:
associated diagnosis of rhabdomyolysis
Observation 2:
Age: 40-49 years
Sex: male
|
|
|
Pathogenic
(Oct 29, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449610.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jun 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523722.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PVS1, PS3, PS4, PM3, PP1
Clinical Features:
Rhabdomyolysis (present) , Myopathy (present) , Exercise intolerance (present) , Elevated circulating creatine kinase concentration (present)
Geographic origin: Brazil
|
|
|
Pathogenic
(Mar 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485127.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893906.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Sep 07, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000740891.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Rhabdomyolysis (present) , Elevated plasma acylcarnitine levels (present) , Anxiety (present) , Palpitations (present) , Premature birth (present) , Obesity (present)
Sex: male
Ethnicity/Population group: Caucasian
|
|
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Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207202.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197312.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type V
Affected status: yes
Allele origin:
paternal
|
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382156.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
ACMG Criteria: PVS1, PS3, PS4, PM3, PP1, PP5; Variant was found in compound heterozygous state with NM_005609.4:c.1477del.
Clinical Features:
Abnormal hepatic glycogen storage (present) , Obesity (present) , Neurodevelopmental delay (present) , Polyphagia (present)
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Pathogenic
(Jul 01, 2007)
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no assertion criteria provided
Method: literature only
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MCARDLE DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022546.5
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2018 |
Comment on evidence:
In a study of 40 patients with McArdle disease (GSD5; 232600), Tsujino et al. (1993) identified 3 distinct point mutations in the PYGM gene. The … (more)
In a study of 40 patients with McArdle disease (GSD5; 232600), Tsujino et al. (1993) identified 3 distinct point mutations in the PYGM gene. The most common mutation was a C-to-T change in exon 1, reported as an ARG49TER (R49X) substitution but now designated R50X. Eighteen patients were homozygous for the R49X mutation, while 12 were compound heterozygous for the R49X mutation and another mutation, thus accounting for 75% of all patients. The second mutation was a G-to-A change in exon 5, resulting in a gly205-to-ser (G205S; 608455.0002) substitution, reported as a GLY204SER (G204S) substitution. The third mutation was an A-to-C change in exon 14, resulting in a lys543-to-thr (L543T) substitution, reported as a LYS542THR (L542T) substitution. Six of the 40 patients had different mutations in the 2 alleles (i.e., were compound heterozygotes), and 11 were presumed to be compound heterozygotes for a known mutation and an unknown one. Only 5 patients had none of the 3 mutations. In 1 remarkable family, all 3 mutations were present in various combinations in 5 members of the family in which transmission appeared to be autosomal dominant. Thus, this was pseudodominance due to mating of a compound heterozygote with a person carrying a third mutation. Three children were all compound heterozygotes, but compound heterozygotes of 2 different compositions. The mother was a 204/49 compound; the father was a 542 carrier; 2 children were 542/204 compounds and 1 was a 542/49 compound. Presumed autosomal dominant inheritance was reported by Chui and Munsat (1976), and the occurrence of McArdle disease in 2 generations was attributed to manifestations in some heterozygotes by Schmidt et al. (1987) and Papadimitriou et al. (1990). Bartram et al. (1993) found the R49X mutation in all 16 McArdle disease patients studied; 10 of the 16 were homozygous, and the remainder were heterozygous, with the other allele awaiting identification. Vorgerd et al. (1998) performed mutation analysis in 9 patients from 8 unrelated German families with typical myophosphorylase deficiency. They found the R49X mutation in homozygous state in 4 patients as well as in compound heterozygous state in 3 others, suggesting that this is the most common mutation associated with myophosphorylase deficiency in Germans. Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with glycogen storage disease V and found the R49X mutation in 70% of patients and 55% of mutant alleles. Martin et al. (2004) demonstrated that the R49X mutation is the most common among Dutch patients with McArdle disease. Andreu et al. (2007) stated that the R49X mutation is now referred to as R50X. The highest frequency of R50X is in Great Britain and North America (81% and 63%, respectively), with approximately 50% frequency in other European countries. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease V
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454306.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554240.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European … (more)
The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760270.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969198.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Oct 18, 2021)
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no assertion criteria provided
Method: clinical testing
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Muscular atrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center
Accession: SCV001980710.1
First in ClinVar: Oct 25, 2021 Last updated: Oct 25, 2021 |
Comment:
The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et … (more)
The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et al., 2015). To date, this variant has eleven independent pathogenic curations in ClinVar (VarID:2298). Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008). (less)
Clinical Features:
Exercise intolerance (present)
Age: 20-29 years
Sex: female
Ethnicity/Population group: Ashkenazi Jewish
Comment on evidence:
Glycolytic enzyme assay in the biopsied muscle revealed undetectable activity of myophosphorylase measured spectrophotometrically. activities of other enzymes (PFK, PGK, CPT, LDH, and PGM) were … (more)
Glycolytic enzyme assay in the biopsied muscle revealed undetectable activity of myophosphorylase measured spectrophotometrically. activities of other enzymes (PFK, PGK, CPT, LDH, and PGM) were normal. Trio whole exome sequencing revealed biallelic variants in PYGM c.[148C>T]:[2082C>A], p.[Arg50Ter]:[Asp694Glu] in this affected individual. (less)
Method: Whole exome sequencing libraries were prepared from genomic DNA from the patient and her parents using Agilent SureSelectXT capture kit according to the manufacturers' protocol. Paired-end sequencing was performed on the Illumina High Seq 2500 platform. The sequence data was aligned and annotated using NextGene (SoftGenetics version 2.3) software.
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Likely pathogenic
(Dec 19, 2022)
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no assertion criteria provided
Method: clinical testing
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Tip-toe gait
Affected status: yes
Allele origin:
germline
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Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV004023192.2
First in ClinVar: Aug 05, 2023 Last updated: Jun 23, 2024 |
Comment:
Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic … (more)
Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research. (less)
Clinical Features:
Pes cavus (present) , Brachydactyly (present) , Bell-shaped thorax (present) , limited range of motion of upper ankle (present)
Method: Gene panel analysis
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807182.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742786.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Glycogen storage disease, type V
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000172194.3
First in ClinVar: Jul 10, 2014 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong.
Comment:
The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2298; PMID: 20301518; PMID: 23653251; PMID: 17324573; PMID: 12929201; PMID:20301518) - PS4. The variant is present at low allele frequencies population databases (rs116987552 – gnomAD 0.01499%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg50*) was detected in trans with a pathogenic variant (PMID: 23653251; PMID: 17324573) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 50 (PVS1). The variant has been reported in probands with a clinical presentation of OMIM:232600 ( Reported multiple times in OMIM:608455 ) (PS4). Well-established functional studies show a deleterious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease ) (PS3). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Identified in another case as compound het with a second pathogenic variant in PYGM (c.613G>A;p.Gly205Ser). This variant was shown to be maternally inherited and the c.613G>A variant is paternally inherited in that case. The variant has been reported in dbSNP (rs116987552) and in the HGMD database: CM930629. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2298).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with McArdle disease (MIM#232600). (I) 0106 - This gene is associated with autosomal recessive disease. However, a single family has been reported for an autosomal dominant glycogen storage disorder (PMID: 32386344). (I) 0115 - Variants in this gene are known to have variable expressivity. Some affected individuals have minimal symptoms with essentially no limitations in activities of daily living. This may be attributed to variable physical activity habits (Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 253 heterozygotes, 1 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Several NMD-predicted variants have been reported in patients with McArdle disease (MIM#232600) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several McArdle disease (MIM#232600) patients in both homozygous and compound heterozygous states (ClinVar; PMID: 29143597). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001969). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25873271, 31980526, 32124677, 31517061, 29961518, 30609409, 30316539, 30415384, 29382405, 22995991, 22344438, 20981092, 18667317, 10918252, 9120482, 27899787, 27300253, 26670295, 27031745, 22730558, 27030740, 22818872, 8316268, 17404776, 25741863, 26240973, 25240406, 25914343, 23653251)
Comment:
PM2, PVS1
Comment:
Variant summary: PYGM c.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0015 in 251452 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease Type V, also known as McArdle disease, (0.0015 vs 0.0035), allowing no conclusion about variant significance. c.148C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type V (example: Cerino_2022). These data indicate that the variant is very likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35741838). Twenty submitters have cited clinical-significance assessments (all pathogenic) for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs116987552, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result in nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. The variant is present in a large population cohort at a frequency of 0.15% (rs116987552, 424/282,854 alleles, 0 homozygotes in gnomAD v2.1), and is the most common pathogenic variant associated with glycogen storage disease type V (also known as McArdle disease) in the European population. The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in many cases with a clinical diagnosis of McArdle disease (PMID: 8316268). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong.
Comment:
PYGM: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Comment:
ACMG classification criteria: PVS1, PS3, PS4, PM3, PP1
Comment:
ACMG Criteria: PVS1, PS3, PS4, PM3, PP1, PP5; Variant was found in compound heterozygous state with NM_005609.4:c.1477del.
Comment:
The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et al., 2015). To date, this variant has eleven independent pathogenic curations in ClinVar (VarID:2298). Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008).
Comment:
Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center
Accession: SCV001980710.1
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Comment:
The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong.
Comment:
The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2298; PMID: 20301518; PMID: 23653251; PMID: 17324573; PMID: 12929201; PMID:20301518) - PS4. The variant is present at low allele frequencies population databases (rs116987552 – gnomAD 0.01499%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg50*) was detected in trans with a pathogenic variant (PMID: 23653251; PMID: 17324573) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 50 (PVS1). The variant has been reported in probands with a clinical presentation of OMIM:232600 ( Reported multiple times in OMIM:608455 ) (PS4). Well-established functional studies show a deleterious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease ) (PS3). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Identified in another case as compound het with a second pathogenic variant in PYGM (c.613G>A;p.Gly205Ser). This variant was shown to be maternally inherited and the c.613G>A variant is paternally inherited in that case. The variant has been reported in dbSNP (rs116987552) and in the HGMD database: CM930629. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2298).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with McArdle disease (MIM#232600). (I) 0106 - This gene is associated with autosomal recessive disease. However, a single family has been reported for an autosomal dominant glycogen storage disorder (PMID: 32386344). (I) 0115 - Variants in this gene are known to have variable expressivity. Some affected individuals have minimal symptoms with essentially no limitations in activities of daily living. This may be attributed to variable physical activity habits (Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 253 heterozygotes, 1 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Several NMD-predicted variants have been reported in patients with McArdle disease (MIM#232600) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several McArdle disease (MIM#232600) patients in both homozygous and compound heterozygous states (ClinVar; PMID: 29143597). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001969). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25873271, 31980526, 32124677, 31517061, 29961518, 30609409, 30316539, 30415384, 29382405, 22995991, 22344438, 20981092, 18667317, 10918252, 9120482, 27899787, 27300253, 26670295, 27031745, 22730558, 27030740, 22818872, 8316268, 17404776, 25741863, 26240973, 25240406, 25914343, 23653251)
Comment:
PM2, PVS1
Comment:
Variant summary: PYGM c.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0015 in 251452 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease Type V, also known as McArdle disease, (0.0015 vs 0.0035), allowing no conclusion about variant significance. c.148C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type V (example: Cerino_2022). These data indicate that the variant is very likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35741838). Twenty submitters have cited clinical-significance assessments (all pathogenic) for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs116987552, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result in nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. The variant is present in a large population cohort at a frequency of 0.15% (rs116987552, 424/282,854 alleles, 0 homozygotes in gnomAD v2.1), and is the most common pathogenic variant associated with glycogen storage disease type V (also known as McArdle disease) in the European population. The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in many cases with a clinical diagnosis of McArdle disease (PMID: 8316268). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong.
Comment:
PYGM: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Comment:
ACMG classification criteria: PVS1, PS3, PS4, PM3, PP1
Comment:
ACMG Criteria: PVS1, PS3, PS4, PM3, PP1, PP5; Variant was found in compound heterozygous state with NM_005609.4:c.1477del.
Comment:
The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et al., 2015). To date, this variant has eleven independent pathogenic curations in ClinVar (VarID:2298). Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008).
Comment:
Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic Profile of Patients with Limb-Girdle Muscle Weakness in the Chilean Population. | Cerino M | Genes | 2022 | PMID: 35741838 |
| A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation. | Echaniz-Laguna A | Annals of neurology | 2020 | PMID: 32386344 |
| Glycogen Storage Disease Type V. | Adam MP | - | 2019 | PMID: 20301518 |
| McArdle's disease: A differential diagnosis of idiopathic toe walking. | Pomarino D | Journal of orthopaedics | 2018 | PMID: 29881221 |
| Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update. | Santalla A | BMC genomics | 2017 | PMID: 29143597 |
| McArdle Disease: Update of Reported Mutations and Polymorphisms in the PYGM Gene. | Nogales-Gadea G | Human mutation | 2015 | PMID: 25914343 |
| Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model. | Brull A | The Journal of physiology | 2015 | PMID: 25873271 |
| Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V. | Hogrel JY | European journal of neurology | 2015 | PMID: 25740218 |
| PYGM expression analysis in white blood cells: a complementary tool for diagnosing McArdle disease? | de Luna N | Neuromuscular disorders : NMD | 2014 | PMID: 25240406 |
| Clinical and molecular characterization of McArdle's disease in Brazilian patients. | Gurgel-Giannetti J | Neuromolecular medicine | 2013 | PMID: 23653251 |
| Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. | Nogales-Gadea G | Brain : a journal of neurology | 2012 | PMID: 22730558 |
| Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. | Lucia A | Journal of neurology, neurosurgery, and psychiatry | 2012 | PMID: 22250184 |
| Molecular and clinical study of McArdle's disease in a cohort of 123 European patients. Identification of 20 novel mutations. | Vieitez I | Neuromuscular disorders : NMD | 2011 | PMID: 21802952 |
| Expression of the muscle glycogen phosphorylase gene in patients with McArdle disease: the role of nonsense-mediated mRNA decay. | Nogales-Gadea G | Human mutation | 2008 | PMID: 17994553 |
| McArdle disease: molecular genetic update. | Andreu AL | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2007 | PMID: 17915571 |
| Analysis of spectrum and frequencies of mutations in McArdle disease. Identification of 13 novel mutations. | Deschauer M | Journal of neurology | 2007 | PMID: 17404776 |
| Molecular characterization of myophosphorylase deficiency (McArdle disease) in 34 patients from Southern France: identification of 10 new mutations. Absence of genotype-phenotype correlation. | Aquaron R | Neuromuscular disorders : NMD | 2007 | PMID: 17324573 |
| A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients. | Rubio JC | Human mutation | 2007 | PMID: 17221871 |
| Novel mutation in the PYGM gene resulting in McArdle disease. | Rubio JC | Archives of neurology | 2006 | PMID: 17172620 |
| McArdle disease: the mutation spectrum of PYGM in a large Italian cohort. | Bruno C | Human mutation | 2006 | PMID: 16786513 |
| Molecular analysis of myophosphorylase deficiency in Dutch patients with McArdle's disease. | Martín MA | Annals of human genetics | 2004 | PMID: 14748827 |
| Two novel mutations in the muscle glycogen phosphorylase gene in McArdle's disease. | Gámez J | Muscle & nerve | 2003 | PMID: 12929201 |
| Molecular heterogeneity of myophosphorylase deficiency (McArdle's disease): a genotype-phenotype correlation study. | Martín MA | Annals of neurology | 2001 | PMID: 11706962 |
| Resolution of a mispaired secondary structure intermediate could account for a novel micro-insertion/deletion (387 insA/del 8 bp) in the PYGM gene causing McArdle's disease. | Martín MA | Clinical genetics | 2001 | PMID: 11168025 |
| Molecular genetic analysis of McArdle's disease in Spanish patients. | Andreu AL | Neurology | 1998 | PMID: 9674815 |
| Mutation analysis in myophosphorylase deficiency (McArdle's disease). | Vorgerd M | Annals of neurology | 1998 | PMID: 9506549 |
| Sudden infant death syndrome (SIDS) in a family with myophosphorylase deficiency. | el-Schahawi M | Neuromuscular disorders : NMD | 1997 | PMID: 9131647 |
| McArdle's disease: a nonsense mutation in exon 1 of the muscle glycogen phosphorylase gene explains some but not all cases. | Bartram C | Human molecular genetics | 1993 | PMID: 8401511 |
| Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). | Tsujino S | The New England journal of medicine | 1993 | PMID: 8316268 |
| McArdle's disease: two clinical expressions in the same pedigree. | Papadimitriou A | Journal of neurology | 1990 | PMID: 2391551 |
| McArdle's disease in two generations: autosomal recessive transmission with manifesting heterozygote. | Schmidt B | Neurology | 1987 | PMID: 3476861 |
| Dominant inheritance of McArdle syndrome. | Chui LA | Archives of neurology | 1976 | PMID: 1067063 |
| - | - | - | - | DOI: 10.1016/j.rchot.2016.09.001 |
| - | - | - | - | DOI: 10.51793/OS.2022.25.6.010 |
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Text-mined citations for rs116987552 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.