Submissions for variant NM_002103.5(GYS1):c.1121A>G (p.Asn374Ser)

gnomAD frequency: 0.00011  dbSNP: rs200672892

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000709981	SCV001216390	uncertain significance	Glycogen storage disease due to muscle and heart glycogen synthase deficiency	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 374 of the GYS1 protein (p.Asn374Ser). This variant is present in population databases (rs200672892, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GYS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 585159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000709981	SCV001293903	uncertain significance	Glycogen storage disease due to muscle and heart glycogen synthase deficiency	2018-01-12	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	RCV001585662	SCV001818068	uncertain significance	not provided	2020-02-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002532900	SCV003695815	uncertain significance	Inborn genetic diseases	2022-12-28	criteria provided, single submitter	clinical testing	The c.1121A>G (p.N374S) alteration is located in exon 8 (coding exon 8) of the GYS1 gene. This alteration results from a A to G substitution at nucleotide position 1121, causing the asparagine (N) at amino acid position 374 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV000709981	SCV000840347	not provided	Glycogen storage disease due to muscle and heart glycogen synthase deficiency		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.