ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs780656375
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Total submissions: 5
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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.
Invitae RCV000670902 SCV002177950 likely pathogenic Glycogen storage disease, type V 2023-06-16 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 555145). This missense change has been observed in individual(s) with McArdle disease (PMID: 17324573, 22250184; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.008%). 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). 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. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Revvity Omics, Revvity Omics 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

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