Submissions for variant NM_001035.3(RYR2):c.9619A>G (p.Asn3207Asp)

gnomAD frequency: 0.00008  dbSNP: rs372601642

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154822	SCV000204504	uncertain significance	not specified	2013-07-29	criteria provided, single submitter	clinical testing	The Asn3207Asp variant in RYR2 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8270 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGV GD) do not provide strong support for or against an impact to the protein, altho ugh 2 species (frog and lamprey carry an aspartic acid (Asp; this variant) at th is position, raising the possibility that this change may be tolerated. Addition al information is needed to fully assess the clinical significance of this varia nt.
GeneDx	RCV000154822	SCV000235013	likely benign	not specified	2014-03-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000266128	SCV000356387	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-13	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	RCV001093778	SCV000356388	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-13	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.
Ambry Genetics	RCV000618927	SCV000737679	likely benign	Cardiovascular phenotype	2023-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001093778	SCV000834214	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2023-10-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777709	SCV000913652	uncertain significance	Cardiomyopathy	2022-12-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 3207 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 been reported in an individual affected with sudden explained death (PMID: 26272908) and in another individual affected with sudden cardiac arrest and Brugada syndrome (PMID: 33652119). This variant has been identified in 14/280404 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000154822	SCV000280457	uncertain significance	not specified	2013-11-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asn3207Asp (c.9619 A>G) in RYR2 (NM_001035.2) I could find no reports associating the variant with disease. In silico analysis with PolyPhen-2 predicts the variant to be benign. The Grantham score is 23. The asparagine at codon 3207 is conserved across species, however in xenopus tropicalis and lamprey there is an aspartate at this residue. I could not find reports of nearby variants associated with disease (in Priori's database http://www.fsm.it/cardmoc/ and http://cardiodb.org/Paralogue_Annotation/gene.php?name=RYR2&display=known). In total the variant has not been seen in 1 of 6036 individuals from publicly available population datasets. The variant was reported online in 1 of 4135 Caucasian individuals and 0 of 1901 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of March 14th, 2014). The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant is in dbSNP (rs372601642) with the only submission being from NHLBI ESP. It is not currently listed as observed in the 1000 genomes dataset (as of March 14th, 2014).