ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6280G>A (p.Gly2094Ser) (rs777365708)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000241874 SCV000319573 uncertain significance Cardiovascular phenotype 2019-03-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000351653 SCV000356331 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 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.
Illumina Clinical Services Laboratory,Illumina RCV001093824 SCV000356332 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 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 RCV000523894 SCV000616858 uncertain significance not provided 2017-09-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The G2094S variant has not been published as pathogenic or been reported as benign to our knowledge. The G2094S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G2094S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across most species with serine (S) being present as the wild type in at least one species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000391795 SCV001199697 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2094 of the RYR2 protein (p.Gly2094Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs777365708, ExAC 0.009%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 263982). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170255 SCV001332815 uncertain significance Cardiomyopathy 2018-10-19 criteria provided, single submitter clinical testing
Color RCV001170255 SCV001358494 uncertain significance Cardiomyopathy 2020-01-15 criteria provided, single submitter clinical testing

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