ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.1349C>T (p.Ser450Leu)

gnomAD frequency: 0.00001  dbSNP: rs756251887
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000338366 SCV000335477 uncertain significance not provided 2015-09-16 criteria provided, single submitter clinical testing
Counsyl RCV000671505 SCV000796488 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 RCV001778878 SCV002015177 uncertain significance not specified 2021-10-04 criteria provided, single submitter clinical testing Variant summary: PYGM c.1349C>T (p.Ser450Leu) 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 3e-05 in 229718 control chromosomes (gnomAD and publication data). c.1349C>T has been reported in the literature in two individuals affected with McArdle disease, including one homozygote (Deschauer_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000671505 SCV002314254 pathogenic Glycogen storage disease, type V 2024-03-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 450 of the PYGM protein (p.Ser450Leu). This variant is present in population databases (rs756251887, gnomAD 0.01%). This missense change has been observed in individual(s) with McArdle disease (PMID: 17404776). ClinVar contains an entry for this variant (Variation ID: 283418). 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.
Baylor Genetics RCV000671505 SCV004207245 likely pathogenic Glycogen storage disease, type V 2024-02-12 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000671505 SCV005374447 likely pathogenic Glycogen storage disease, type V 2024-09-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000671505 SCV005684142 likely pathogenic Glycogen storage disease, type V 2024-06-19 criteria provided, single submitter clinical testing

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