ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.475G>A (p.Gly159Arg)

gnomAD frequency: 0.00001  dbSNP: rs760654579
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671611 SCV000796599 uncertain significance Glycogen storage disease, type V 2017-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282315 SCV002572340 uncertain significance not specified 2022-08-25 criteria provided, single submitter clinical testing Variant summary: PYGM c.475G>A (p.Gly159Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475G>A has been reported in the literature in at-least one allele of an individual affected with Glycogen Storage Disease, Type V (example, Bruno_2006 cited in Nogales-Gadea_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000671611 SCV003248265 pathogenic Glycogen storage disease, type V 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 159 of the PYGM protein (p.Gly159Arg). This variant is present in population databases (rs760654579, gnomAD 0.01%). This missense change has been observed in individual(s) with exercise related rhabdomyolysis and/or McArdle disease (PMID: 16786513; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555738). 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.

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