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

gnomAD frequency: 0.00006  dbSNP: rs201600087

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001258370	SCV001223289	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-30	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, 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.