Submissions for variant NM_005609.4(PYGM):c.877C>T (p.Arg293Trp)

gnomAD frequency: 0.00009  dbSNP: rs558267822

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000313797	SCV000373030	uncertain significance	Glycogen storage disease, type V	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000522784	SCV000618216	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000313797	SCV001044257	likely benign	Glycogen storage disease, type V	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229955	SCV002511719	uncertain significance	not specified	2022-04-19	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.877C>T (p.Arg293Trp) 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 0.00036 in 250324 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00036 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.877C>T in individuals affected with Glycogen Storage Disease, Type V and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: three classify the variant as VUS while one classifies it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000313797	SCV003810374	uncertain significance	Glycogen storage disease, type V	2023-09-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000313797	SCV001452664	uncertain significance	Glycogen storage disease, type V	2020-04-14	no assertion criteria provided	clinical testing