ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.14875C>T (p.Arg4959Trp)

gnomAD frequency: 0.00004  dbSNP: rs755308070
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000774059 SCV000907759 likely benign Cardiomyopathy 2018-10-05 criteria provided, single submitter clinical testing
Invitae RCV001426866 SCV001629527 likely benign Catecholaminergic polymorphic ventricular tachycardia 2021-11-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282363 SCV002572229 likely benign not specified 2022-08-22 criteria provided, single submitter clinical testing Variant summary: RYR2 c.14875C>T (p.Arg4959Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248326 control chromosomes. The observed variant frequency is approximately 1.76 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.14875C>T has been reported in the literature without strong evidence for causality (Landstrom_2017). This report does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV002388395 SCV002700852 uncertain significance Cardiovascular phenotype 2020-12-03 criteria provided, single submitter clinical testing The p.R4959W variant (also known as c.14875C>T), located in coding exon 105 of the RYR2 gene, results from a C to T substitution at nucleotide position 14875. The arginine at codon 4959 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in an exome testing cohort; however clinical details were not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]). An alternate amino acid substitution at this position, p.R4959Q, has been reported in catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS) cohorts (Laitinen PJ et al. Eur. J. Hum. Genet., 2003 Nov;11:888-91; Medeiros-Domingo A et al. J. Am. Coll. Cardiol., 2009 Nov;54:2065-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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