Submissions for variant NM_021957.4(GYS2):c.1436C>A (p.Pro479Gln)

gnomAD frequency: 0.00009  dbSNP: rs121918420

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000017429	SCV000377428	likely pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2024-07-22	criteria provided, single submitter	clinical testing
Invitae	RCV000017429	SCV000763893	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2022-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GYS2 function (PMID: 9691087). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16051). This missense change has been observed in individual(s) with glycogen storage disease type 0 (PMID: 9691087). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918420, gnomAD 0.03%). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 479 of the GYS2 protein (p.Pro479Gln).
GeneDx	RCV001582484	SCV001811915	pathogenic	not provided	2018-10-11	criteria provided, single submitter	clinical testing	Published expression studies demonstrate that variant is associated with no detectable glycogen synthase activity (Orho et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9691087)
3billion	RCV000017429	SCV003841410	likely pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 9691087). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GYS2 related disorder (ClinVar ID: VCV000016051 / PMID: 9691087). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 9691087). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000017429	SCV003933998	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2023-05-19	criteria provided, single submitter	clinical testing	Variant summary: GYS2 c.1436C>A (p.Pro479Gln) 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 6.5e-05 in 245762 control chromosomes (gnomAD). c.1436C>A has been reported in the literature as a compound heterozygous genotype in at least five individuals affected with Glycogen Storage Disorder type 0, including at least two cases where it was confirmed to be in trans with a pathogenic variant (e.g. Orho_1998, Tagliaferri_2022). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function found that the variant resulted in no detectable glycogen synthase activity (Orho_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9691087, 35854365). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2)/likely pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000017429	SCV000037701	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	1998-08-01	no assertion criteria provided	literature only