ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6298C>T (p.Arg2100Trp)

dbSNP: rs753164125
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781823 SCV000920163 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: RYR2 c.6298C>T (p.Arg2100Trp) 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 2e-05 in 246108 control chromosomes. The observed variant frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy (0.000025), suggesting that the variant is possibly benign. Although the total number of occurrence is small. To our knowledge, no occurrence of c.6298C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001182977 SCV001348616 uncertain significance Cardiomyopathy 2023-08-09 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 2100 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 5/249132 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV002535700 SCV001496135 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-04-29 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 633399). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2100 of the RYR2 protein (p.Arg2100Trp). This variant is present in population databases (rs753164125, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. 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.
Ambry Genetics RCV002352299 SCV002655954 uncertain significance Cardiovascular phenotype 2022-03-21 criteria provided, single submitter clinical testing The p.R2100W variant (also known as c.6298C>T), located in coding exon 41 of the RYR2 gene, results from a C to T substitution at nucleotide position 6298. The arginine at codon 2100 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002487612 SCV002790132 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-11-14 criteria provided, single submitter clinical testing

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