Submissions for variant NM_005609.4(PYGM):c.2392T>A (p.Trp798Arg)

dbSNP: rs119103258

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000631182	SCV000752186	pathogenic	Glycogen storage disease, type V	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 798 of the PYGM protein (p.Trp798Arg). This variant is present in population databases (rs119103258, gnomAD 0.07%). This missense change has been observed in individuals with McArdle disease (PMID: 17630210, 17994553, 21802952). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 526617). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000631182	SCV002572302	pathogenic	Glycogen storage disease, type V	2022-08-24	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.2392T>A (p.Trp798Arg) 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 8.7e-05 in 251496 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (8.7e-05 vs 0.0035), allowing no conclusion about variant significance. A different nucleotide change c.2392T>C, also resulting in the same amino acid change has also been reported in individuals affected with Glycogen Storage Disease, Type V (Mc Ardle Disease). p.Trp798Arg has been reported in the literature (nucleotide change not specified) in homozygous and compound heterozygous genotypes in multiple individuals predominantly of Spanish origin affected with Glycogen Storage Disease, Type V (Mc Ardle Disease) (example, Lucia_2007, Vieitez_2011, Garcia-Consuegra_2016). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000631182	SCV004207284	pathogenic	Glycogen storage disease, type V	2023-04-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000631182	SCV001461269	pathogenic	Glycogen storage disease, type V	2020-09-16	no assertion criteria provided	clinical testing