Submissions for variant NM_001035.3(RYR2):c.13718G>A (p.Arg4573His)

gnomAD frequency: 0.00008  dbSNP: rs371157286

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001093841	SCV000356473	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000344574	SCV000356474	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001093841	SCV000637515	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177067	SCV001341195	uncertain significance	Cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 4573 of 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 an individual affected with sudden cardiac death (PMID: 33919104). This variant has been identified in 8/280074 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.
GeneDx	RCV001590913	SCV001825161	uncertain significance	not provided	2020-02-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 296764; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009)
MGZ Medical Genetics Center	RCV000344574	SCV002581248	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2021-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379165	SCV002697205	uncertain significance	Cardiovascular phenotype	2023-12-08	criteria provided, single submitter	clinical testing	The p.R4573H variant (also known as c.13718G>A), located in coding exon 94 of the RYR2 gene, results from a G to A substitution at nucleotide position 13718. The arginine at codon 4573 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with other variants in cardiac-related genes in an individual from a sudden death cohort (Iglesias M et al. J Clin Med, 2021 Apr;10). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002502178	SCV002814061	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995832	SCV004819904	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 4573 of 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/280074 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.