Submissions for variant NM_005609.4(PYGM):c.2143C>T (p.Arg715Trp)

gnomAD frequency: 0.00003  dbSNP: rs780656375

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670902	SCV000795815	likely pathogenic	Glycogen storage disease, type V	2017-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670902	SCV002074524	likely pathogenic	Glycogen storage disease, type V	2022-01-04	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.2143C>T (p.Arg715Trp) 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 8e-06 in 251478 control chromosomes. c.2143C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type V (McArdle disease or myophosphorylase deficiency) (example, Aquaron_2007, Lucia_2012). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670902	SCV002177950	likely pathogenic	Glycogen storage disease, type V	2024-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 715 of the PYGM protein (p.Arg715Trp). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with McArdle disease (PMID: 17324573, 22250184; Invitae). ClinVar contains an entry for this variant (Variation ID: 555145). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PYGM protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000670902	SCV003810386	uncertain significance	Glycogen storage disease, type V	2023-05-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670902	SCV004207200	pathogenic	Glycogen storage disease, type V	2023-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV004812348	SCV005437437	likely pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; 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: 31589614, 36890159, 33234167, 32153140, 17324573, 18808785, 22250184, 29143597)
Fulgent Genetics, Fulgent Genetics	RCV000670902	SCV005684074	likely pathogenic	Glycogen storage disease, type V	2024-05-30	criteria provided, single submitter	clinical testing