ClinVar Genomic variation as it relates to human health
NM_013382.7(POMT2):c.1997A>G (p.Tyr666Cys)
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_013382.7(POMT2):c.1997A>G (p.Tyr666Cys)
Variation ID: 3221 Accession: VCV000003221.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 77278764 (GRCh38) [ NCBI UCSC ] 14: 77745107 (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 Oct 23, 2014 Feb 28, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_013382.7:c.1997A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_037514.2:p.Tyr666Cys missense NC_000014.9:g.77278764T>C NC_000014.8:g.77745107T>C NG_008897.1:g.47119A>G LRG_844:g.47119A>G LRG_844t1:c.1997A>G LRG_844p1:p.Tyr666Cys Q9UKY4:p.Tyr666Cys - Protein change
- Other names
- Y666C
- p.Y666C:TAC>TGC
- NM_013382.5(POMT2):c.1997A>G(p.Tyr666Cys)
- Canonical SPDI
- NC_000014.9:77278763:T:C
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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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
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. |
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POMT2 | - | - |
GRCh38 GRCh37 |
1123 | 1192 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Oct 30, 2023 | RCV000003377.12 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 31, 2018 | RCV000003376.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 26, 2022 | RCV000081569.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2015 | RCV000193219.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 9, 2021 | RCV000515301.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000648175.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV003398429.4 |
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. |
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Pathogenic
(Jul 01, 2015)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248592.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jan 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331113.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 8
Sex: mixed
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Pathogenic
(May 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019498.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Dec 01, 2015)
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criteria provided, single submitter
Method: research
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
Affected status: yes
Allele origin:
unknown
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Center for Genetic Medicine Research, Children's National Medical Center
Accession: SCV000265767.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 06, 2016 |
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Likely pathogenic
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803551.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
Comment:
This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2, in Autosomal Recessive manner. The following ACMG … (more)
This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:17634419,19138766). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:17878207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Found in multiple unrelated patients (PMID:17878207,17634419,19138766,19299310). (less)
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Pathogenic
(Aug 06, 2020)
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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: SCV000196887.14
First in ClinVar: Jan 23, 2015 Last updated: Apr 17, 2019 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17634419, 30060766, 24002165, 19299310, 28980384, 29175898, 17878207, 19138766, 17869517, 27854218, 32115343, 31127727, 31589614, 32528171) (less)
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Pathogenic
(Aug 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 Autosomal recessive limb-girdle muscular dystrophy type 2N
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611299.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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POMT2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104804.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The POMT2 c.1997A>G variant is predicted to result in the amino acid substitution p.Tyr666Cys. This variant has been reported in the homozygous or compound heterozygous … (more)
The POMT2 c.1997A>G variant is predicted to result in the amino acid substitution p.Tyr666Cys. This variant has been reported in the homozygous or compound heterozygous state in many individuals with POMT2-related disorders (Yanagisawa et al. 2007. PubMed ID: 17634419; Godfrey et al. 2007. PubMed ID: 17878207; Martinez et al. 2013. PubMed ID: 24002165; Østergaard et al. 2017. PubMed ID: 29175898; Westra et al. 2019. PubMed ID: 31127727; Saat et al. 2021. PubMed ID: 33963534; Punetha et al. 2016. PubMed ID: 27854218). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-77745107-T-C). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204084.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 Autosomal recessive limb-girdle muscular dystrophy type 2N
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000769989.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 666 of the POMT2 protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 666 of the POMT2 protein (p.Tyr666Cys). This variant is present in population databases (rs200198778, gnomAD 0.02%). This missense change has been observed in individuals with congenital muscular dystrophy (PMID: 17634419, 17878297, 24002165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POMT2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023535.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2014 |
Comment on evidence:
In 2 unrelated patients with congenital muscular dystrophy and severe mental retardation (MDDGB2; 613156), Yanagisawa et al. (2007) identified a homozygous 1997A-G transition in exon … (more)
In 2 unrelated patients with congenital muscular dystrophy and severe mental retardation (MDDGB2; 613156), Yanagisawa et al. (2007) identified a homozygous 1997A-G transition in exon 19 of the POMT2 gene, resulting in a tyr666-to-cys (Y666C) substitution in a highly conserved residue. The patients were of Moroccan and French descent, respectively. Haplotype analysis indicated a founder effect. Two additional patients with a similar phenotype were compound heterozygous for Y666C and another pathogenic POMT2 mutation (W647X; 607439.0005 and W748R; 607439.0006). Godfrey et al. (2007) identified a homozygous Y666C substitution in 2 sibs with congenital muscular dystrophy and low IQ. Both patients had onset in infancy and increased serum creatine kinase. One achieved walking, the other sitting. One had contractures, muscle hypertrophy, and microcephaly. The other had hypoplastic cerebellum, micropenis, and cryptorchidism. Godfrey et al. (2007) identified a homozygous Y666C mutation in a patient classified as having muscle-eye-brain disease (MDDGA2; 613150). The patient, who reportedly had onset at age 4 years, never achieved walking, and had increased serum creatine kinase, muscle hypertrophy, microcephaly, low IQ, and encephalocele. Two additional patients with muscle-eye-brain disease were compound heterozygous for Y666C and another pathogenic POMT2 mutation (see, e.g., R413P; 607439.0007). Mercuri et al. (2009) identified compound heterozygosity for Y666C and G246D (607439.0016) in an Italian patient with congenital muscular dystrophy, microcephaly, mental retardation, but normal brain MRI with minimal white matter changes. Yanagisawa et al. (2009) reported 3 unrelated French patients who were compound heterozygous for the Y666C mutation and another pathogenic mutation in the POMT2 gene. Two patients with MDDGB2 were compound heterozygous for Y666C and another pathogenic mutation (see, e.g., 607439.0017), whereas the third had the more severe MDDGA2 phenotype and carried Y666C and a deletion of several exons of the POMT2 gene. (less)
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023534.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 24, 2020 |
Comment on evidence:
In 2 unrelated patients with congenital muscular dystrophy and severe mental retardation (MDDGB2; 613156), Yanagisawa et al. (2007) identified a homozygous 1997A-G transition in exon … (more)
In 2 unrelated patients with congenital muscular dystrophy and severe mental retardation (MDDGB2; 613156), Yanagisawa et al. (2007) identified a homozygous 1997A-G transition in exon 19 of the POMT2 gene, resulting in a tyr666-to-cys (Y666C) substitution in a highly conserved residue. The patients were of Moroccan and French descent, respectively. Haplotype analysis indicated a founder effect. Two additional patients with a similar phenotype were compound heterozygous for Y666C and another pathogenic POMT2 mutation (W647X; 607439.0005 and W748R; 607439.0006). Godfrey et al. (2007) identified a homozygous Y666C substitution in 2 sibs with congenital muscular dystrophy and low IQ. Both patients had onset in infancy and increased serum creatine kinase. One achieved walking, the other sitting. One had contractures, muscle hypertrophy, and microcephaly. The other had hypoplastic cerebellum, micropenis, and cryptorchidism. Godfrey et al. (2007) identified a homozygous Y666C mutation in a patient classified as having muscle-eye-brain disease (MDDGA2; 613150). The patient, who reportedly had onset at age 4 years, never achieved walking, and had increased serum creatine kinase, muscle hypertrophy, microcephaly, low IQ, and encephalocele. Two additional patients with muscle-eye-brain disease were compound heterozygous for Y666C and another pathogenic POMT2 mutation (see, e.g., R413P; 607439.0007). Mercuri et al. (2009) identified compound heterozygosity for Y666C and G246D (607439.0016) in an Italian patient with congenital muscular dystrophy, microcephaly, mental retardation, but normal brain MRI with minimal white matter changes. Yanagisawa et al. (2009) reported 3 unrelated French patients who were compound heterozygous for the Y666C mutation and another pathogenic mutation in the POMT2 gene. Two patients with MDDGB2 were compound heterozygous for Y666C and another pathogenic mutation (see, e.g., 607439.0017), whereas the third had the more severe MDDGA2 phenotype and carried Y666C and a deletion of several exons of the POMT2 gene. (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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Targeted Re-Sequencing Emulsion PCR Panel for Myopathies: Results in 94 Cases. | Punetha J | Journal of neuromuscular diseases | 2016 | PMID: 27854218 |
Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. | Mercuri E | Neurology | 2009 | PMID: 19299310 |
POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation. | Yanagisawa A | European journal of medical genetics | 2009 | PMID: 19138766 |
IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs. | Tritsaris K | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17878297 |
Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. | Godfrey C | Brain : a journal of neurology | 2007 | PMID: 17878207 |
New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation. | Yanagisawa A | Neurology | 2007 | PMID: 17634419 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POMT2 | - | - | - | - |
Text-mined citations for rs200198778 ...
HelpRecord last updated Apr 20, 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.