Submissions for variant NM_001035.3(RYR2):c.982G>A (p.Ala328Thr)

gnomAD frequency: 0.00004  dbSNP: rs201669522

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079381	SCV000111260	uncertain significance	not provided	2013-11-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001093747	SCV000356205	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	RCV000391386	SCV000356206	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.
Invitae	RCV001093747	SCV000760597	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-12-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189215	SCV001356460	uncertain significance	Cardiomyopathy	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 328 of the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 3/248122 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.
Fulgent Genetics, Fulgent Genetics	RCV002498396	SCV002815562	uncertain significance	Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	2021-09-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003380409	SCV004089858	uncertain significance	Cardiovascular phenotype	2023-08-10	criteria provided, single submitter	clinical testing	The p.A328T variant (also known as c.982G>A), located in coding exon 12 of the RYR2 gene, results from a G to A substitution at nucleotide position 982. The alanine at codon 328 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a Wolff Parkinson White cohort (Coban-Akdemir ZH et al. Am J Med Genet A, 2020 Jun;182:1387-1399). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000079381	SCV004224828	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	PP2
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656194	SCV000678388	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome