ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.1147G>A (p.Glu383Lys)

gnomAD frequency: 0.00001  dbSNP: rs757681143
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494108 SCV000582886 likely pathogenic not provided 2021-01-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22250184, 16793208, 29143597, 17404776)
Invitae RCV001036939 SCV001200328 pathogenic Glycogen storage disease, type V 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 383 of the PYGM protein (p.Glu383Lys). This variant is present in population databases (rs757681143, gnomAD 0.006%). This missense change has been observed in individual(s) with myophosphorylase deficiency (PMID: 16793208, 17404776, 22250184, 29143597). ClinVar contains an entry for this variant (Variation ID: 430154). 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 PYGM protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Preventiongenetics, part of Exact Sciences RCV003409682 SCV004112548 likely pathogenic PYGM-related condition 2023-02-08 criteria provided, single submitter clinical testing The PYGM c.1147G>A variant is predicted to result in the amino acid substitution p.Glu383Lys. This variant was reported in two individuals with McArdle disease. In both patients, myophosphorylase deficiency was proven either biochemically using muscle biopsy or by histochemical staining revealing absent phosphorylase. Both patients were also carrier of the c.1155_1156delGG pathogenic variant. It is unclear if the variants were found on opposite alleles (Patients 3 and 5, Rommel et al. 2006. PubMed ID: 16793208). The p.Glu383Lys variant has also been reported, along with the p.Arg50* common pathogenic variant, in three Spanish patients with McArdle disease (Santalla et al. 2017. PubMed ID: 29143597). This variant is reported in 0.0052% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64521443-C-T). This variant is interpreted as likely pathogenic.
Baylor Genetics RCV001036939 SCV004207232 likely pathogenic Glycogen storage disease, type V 2023-09-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001036939 SCV004241142 likely pathogenic Glycogen storage disease, type V 2023-12-15 criteria provided, single submitter clinical testing Variant summary: PYGM c.1147G>A (p.Glu383Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-06 in 234212 control chromosomes (gnomAD). c.1147G>A has been reported in the literature in individuals affected with McArdle disease (examples: Rommel_2006, Lucia_2012, Santalla_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22250184, 16793208, 29143597). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001036939 SCV001461284 likely pathogenic Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing

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