Submissions for variant NM_001035.3(RYR2):c.13175A>G (p.Lys4392Arg)

gnomAD frequency: 0.00003  dbSNP: rs753733164

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001101826	SCV000826858	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101825	SCV001258466	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101826	SCV001258467	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001181816	SCV001347050	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated Japanese affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 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.
Ambry Genetics	RCV002386225	SCV002689697	uncertain significance	Cardiovascular phenotype	2021-03-08	criteria provided, single submitter	clinical testing	The p.K4392R variant (also known as c.13175A>G), located in coding exon 90 of the RYR2 gene, results from an A to G substitution at nucleotide position 13175. The lysine at codon 4392 is replaced by arginine, an amino acid with highly similar properties. This variant has been detected in the heterozygous state in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) and in asymptomatic relatives (Arakawa J et al. Heart Vessels, 2015 Nov;30:835-40; Kawata H et al. Circ J, 2016 Aug;80:1907-15; Kawamura M et al. Circ J, 2013 Apr;77:1705-13). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235360	SCV003934703	benign	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.13175A>G (p.Lys4392Arg) results in a conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 324312 control chromosomes, including 2 homozygotes (gnomAD and jMorp databases (Tadaka_2021)). The observed variant frequency is approximately 41.62 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.13175A>G has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia, however, the variant was also identified in unaffected individuals and found to not segregate with disease among related individuals (e.g., Kawamura_2013, Arakawa_2015). Additionally, in one proband with catecholaminergic polymorphic ventricular tachycardia, a co-occurrence with another pathogenic variant was reported (RYR2 c.12006G>A, p.M4002I; Kawamura_2013), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant showed no damaging effect on the cytosolic calcium-dependent activity of RYR2 (e.g., Kurebayashi_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25092222, 23595086, 35446340, 33179747). Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: 3 submitters classified the variant as uncertain significance, and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as benign.
All of Us Research Program, National Institutes of Health	RCV003999677	SCV004821097	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2023-10-02	criteria provided, single submitter	clinical testing	This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated Japanese affected with catecholaminergic polymorphic ventricular tachycardia, as well as in a few asymptomatic carriers in their families (PMID: 23595086, 25092222). This variant has also been reported in an individual affected with idiopathic bradyarrhythmia (PMID: 36070930). This variant has been identified in 4/246870 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.
Breakthrough Genomics, Breakthrough Genomics	RCV004691284	SCV005186377	uncertain significance	not provided		criteria provided, single submitter	not provided