Submissions for variant NM_002103.5(GYS1):c.678+1G>A

gnomAD frequency: 0.00006  dbSNP: rs755305465

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061520	SCV001226265	pathogenic	Glycogen storage disease due to muscle and heart glycogen synthase deficiency	2024-10-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the GYS1 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 GYS1 are known to be pathogenic (PMID: 17928598, 19699667). This variant is present in population databases (rs755305465, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with muscle glycogen synthase deficiency (PMID: 35641353). ClinVar contains an entry for this variant (Variation ID: 856123). Studies have shown that disruption of this splice site alters GYS1 gene expression (PMID: 35641353). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001061520	SCV002024935	pathogenic	Glycogen storage disease due to muscle and heart glycogen synthase deficiency	2020-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001061520	SCV003922860	likely pathogenic	Glycogen storage disease due to muscle and heart glycogen synthase deficiency	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: GYS1 c.678+1G>A 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. The TraP (transcript-inferred pathogenicity) in silico prediction tool scores the variant as probably pathogenic. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251360 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.678+1G>A in individuals affected with GYS1-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant affecting the same nucleotide, c.678+1G>C, has been reported in a homozygous individual with adult-onset myopathy without cardiomyopathy (PMID: 35641353). Two ClinVar submitters (evaluation after 2014) have cited the variant, and both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.