Submissions for variant NM_021957.4(GYS2):c.495+1G>T

gnomAD frequency: 0.00009  dbSNP: rs372079212

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000823292	SCV000964146	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2022-03-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 665082). Disruption of this splice site has been observed in individuals with glycogen storage disease (PMID: 25070466; Invitae). This variant is present in population databases (rs372079212, gnomAD 0.02%). This sequence change affects a donor splice site in intron 3 of the GYS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252252	SCV002523873	likely pathogenic	See cases	2020-11-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2, PM3
Fulgent Genetics, Fulgent Genetics	RCV000823292	SCV002806245	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2021-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000823292	SCV002819370	likely pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: GYS2 c.495+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.6e-05 in 250990 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. c.495+1G>T has been reported in the literature in the compound heterozygous state in at least one individual affected with Glycogen Storage Disorder Due To Hepatic Glycogen Synthase Deficiency (GSD0) (e.g. Weinstein_2006, Brown_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.