ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1511G>A (p.Arg504His)

gnomAD frequency: 0.00006  dbSNP: rs201600087
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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 RCV000781822 SCV000920162 likely benign not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: RYR2 c.1511G>A (p.Arg504His) results in a non-conservative amino acid change located in the RIH domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 273504 control chromosomes. The observed variant frequency is approximately 4.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1511G>A has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (ALMS1 c.3569delT, Phe1192fsX73), providing supporting evidence for a benign role although the possibility of an incidental carrier status for autosomal recessive Alstrom syndrome cannot be ruled out. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 likely benign.
Invitae RCV001258370 SCV001223289 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001187355 SCV001354129 likely benign Cardiomyopathy 2023-04-28 criteria provided, single submitter clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV001258370 SCV001435341 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2020-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002388409 SCV002709783 uncertain significance Cardiovascular phenotype 2023-05-10 criteria provided, single submitter clinical testing The p.R504H variant (also known as c.1511G>A), located in coding exon 16 of the RYR2 gene, results from a G to A substitution at nucleotide position 1511. The arginine at codon 504 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in a whole exome cohort; however, cardiac details were not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10:[Epub ahead of print]). This amino acid position is highly 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.

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