ClinVar Genomic variation as it relates to human health
NM_021957.4(GYS2):c.736C>T (p.Arg246Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_021957.4(GYS2):c.736C>T (p.Arg246Ter)
Variation ID: 16049 Accession: VCV000016049.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 21568952 (GRCh38) [ NCBI UCSC ] 12: 21721886 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 5, 2014 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021957.4:c.736C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068776.2:p.Arg246Ter nonsense NC_000012.12:g.21568952G>A NC_000012.11:g.21721886G>A NG_016167.1:g.40896C>T LRG_1293:g.40896C>T LRG_1293t1:c.736C>T LRG_1293p1:p.Arg246Ter - Protein change
- R246*
- Other names
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- Canonical SPDI
- NC_000012.12:21568951:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00038
Exome Aggregation Consortium (ExAC) 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GYS2 | - | - |
GRCh38 GRCh37 |
251 | 318 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000017427.45 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2015 | RCV000605157.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV003944826.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2022 | RCV002251426.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2021 | RCV002251909.2 |
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
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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
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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
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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. |
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914580.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GYS2 c.736C>T (p.Arg246Ter) variant is a stop-gained variant that has been reported in five studies in which it is found in a total of … (more)
The GYS2 c.736C>T (p.Arg246Ter) variant is a stop-gained variant that has been reported in five studies in which it is found in a total of six individuals from five unrelated families affected with the liver presentation of glycogen storage disease type 0 (GSD 0), including three individuals who carried the variant in a homozygous state (including one sibling pair), and in three individuals who carried the variant in a compound heterozygous state (Orho et al. 1998; Bachrach et al. 2002; Soggia et al. 2010; Brown et al. 2015; Kasapkara et al. 2017). The p.Arg246Ter variant was also detected in a heterozygous state in five family members of patients, one of whom was described as glucose intolerant. The variant was absent from 400 control chromosomes and is reported at a frequency of 0.002047 in the South Asian population of the Genome Aggregation Database. There is one homozygote present in the Genome Aggregation Database which can be explained by the variable presentation of liver GSD 0 which may go undetected even in adulthood. Based on the collective evidence, the c.736C>T (p.Arg246Ter) variant is classified as pathogenic for the liver form of glycogen storage disease type 0. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Dec 17, 2015)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711744.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg246X variant in GYS2 has been reported in 2 individuals with glycogen s torage disease type 0, one of whom was homozygous and one … (more)
The p.Arg246X variant in GYS2 has been reported in 2 individuals with glycogen s torage disease type 0, one of whom was homozygous and one was compound heterozyg ous for this variant (Ohno 1998 and Soggia 2010). This variant has also been ide ntified in 0.2% (31/16479) of South Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121918419). This nonsen se variant leads to a premature termination codon at position 246, which is pred icted to lead to a truncated or absent protein. Loss of function of the GYS2 gen e is associated with glycogen storage disease type 0. In summary, although addit ional studies are required to fully establish its clinical significance, the p.A rg246X variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768259.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, 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_v1.3.4, 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 liver glycogen storage disease 0 (MIM#240600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable clinical phenotypes have been reported in affected individuals within the same family (PMIDs: 18341095, 28245189, 32395408). (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 (v2) <0.01 for a recessive condition (98 heterozygotes, 1 homozygote). (SP) 0701 - Other variants resulting in a premature termination codon comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least 10 other NMD-predicted variants have been reported in affected individuals (PMID: 32779500) or as likely pathogenic/pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with glycogen synthase deficiency (PMIDs: 12072888, 28245189, 32779500) and as likely pathogenic/pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002521980.2
First in ClinVar: Jun 05, 2022 Last updated: Mar 04, 2023 |
Comment:
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; Published … (more)
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; Published functional studies demonstrate a damaging effect: severely impaired glycogen synthase activity (Orho et al., 1998); This variant is associated with the following publications: (PMID: 25525159, 31589614, 32374048, 20051115, 29961766, 28245189, 30609409, 30487145, 31980526, 9691087) (less)
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Pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933997.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: GYS2 c.736C>T (p.Arg246X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for … (more)
Variant summary: GYS2 c.736C>T (p.Arg246X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00038 in 251426 control chromosomes in the gnomAD database, including 1 homozygote. As the exact prevalence of this disorder is not established, this frequency does not allow conclusions about variant significance. c.736C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disorder Due To Hepatic Glycogen Synthase Deficiency (example, Orho_1998, Bachrach_2002, Soggia_2010, Cakar_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Orho_1998). The most pronounced variant effect results in complete abolishment of normal Glycogen synthase activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 12072888, 32374048, 33502066, 9691087, 20051115). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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GYS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004766207.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GYS2 c.736C>T variant is predicted to result in premature protein termination (p.Arg246*). This variant has been reported in the homozygous and compound heterozygous state … (more)
The GYS2 c.736C>T variant is predicted to result in premature protein termination (p.Arg246*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with glycogen storage disease (see for example, Figure 1, Orho et al. 1998. PubMed ID: 9691087; Bachrach et al. 2002. PubMed ID: 12072888; Figure 1, Soggia et al. 2010. PubMed ID: 20051115). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in GYS2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893971.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002059053.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016049, PMID:9691087). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000354, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Clubfoot (present) , Disproportionate short stature (present)
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Pathogenic
(Apr 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523123.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PVS1, PM3
Clinical Features:
Neoplasm (present) , Abnormality of the cardiovascular system (present) , Short stature (present)
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Pathogenic
(Jul 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024939.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000812768.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg246*) in the GYS2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg246*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs121918419, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with glycogen storage disease type 0 (PMID: 9691087, 20051115, 25070466). ClinVar contains an entry for this variant (Variation ID: 16049). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809852.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Aug 01, 1998)
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no assertion criteria provided
Method: literature only
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GLYCOGEN STORAGE DISEASE 0, LIVER
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037699.2
First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014 |
Comment on evidence:
In a male child born to unrelated Turkish parents living in Austria, Orho et al. (1998) demonstrated that liver glycogen storage disease type 0 (GSD0A; … (more)
In a male child born to unrelated Turkish parents living in Austria, Orho et al. (1998) demonstrated that liver glycogen storage disease type 0 (GSD0A; 240600) was associated with homozygosity for a mutation causing a premature stop codon in exon 5 of the GYS2 gene: arg246-to-ter (CGA-to-TGA). Two of his unaffected brothers carried the arg246-to-ter mutation on 1 allele. The patient had been referred at the age of 4 because of short stature. Serum growth hormone concentration was subnormal. After an overnight fast, the blood glucose was abnormally low, whereas free fatty acids and beta-hydroxybutyrate concentrations were high. In relation to the hypoglycemia, plasma insulin levels were appropriately reduced. An oral glucose tolerance test provoked an excessive rise of blood glucose and lactate, whereas free fatty acids and beta-hydroxybutyrate were normal. At age 7, a liver biopsy showed low glycogen synthase activity with glycogen content in the low to normal range. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians. | Kausthubham N | Human mutation | 2021 | PMID: 33502066 |
A patient with glycogen storage disease type 0 and a novel sequence variant in GYS2: a case report and literature review. | Arko JJ | The Journal of international medical research | 2020 | PMID: 32779500 |
Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants. | Kamenets EA | JIMD reports | 2020 | PMID: 32395408 |
Novel variants in Turkish patients with glycogen storage disease. | Çakar NE | Pediatrics international : official journal of the Japan Pediatric Society | 2020 | PMID: 32374048 |
The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency. | Kasapkara ÇS | Journal of pediatric endocrinology & metabolism : JPEM | 2017 | PMID: 28245189 |
Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. | Brown LM | Journal of inherited metabolic disease | 2015 | PMID: 25070466 |
A novel mutation in the glycogen synthase 2 gene in a child with glycogen storage disease type 0. | Soggia AP | BMC medical genetics | 2010 | PMID: 20051115 |
The variable clinical phenotype of liver glycogen synthase deficiency. | Spiegel R | Journal of pediatric endocrinology & metabolism : JPEM | 2007 | PMID: 18341095 |
Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. | Bachrach BE | The Journal of pediatrics | 2002 | PMID: 12072888 |
Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. | Orho M | The Journal of clinical investigation | 1998 | PMID: 9691087 |
Text-mined citations for rs121918419 ...
HelpRecord last updated Apr 15, 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.