Submissions for variant NM_001035.3(RYR2):c.3251G>A (p.Arg1084Lys)

gnomAD frequency: 0.00013  dbSNP: rs193922624

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171675	SCV000055282	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036727	SCV000060382	likely benign	not specified	2014-01-21	criteria provided, single submitter	clinical testing	Arg1084Lys in exon 28 of RYR2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, opossum, tasmanian devil, and wallaby have a lysine (Lys) at this position a s well as several birds and reptiles despite high nearby amino acid conservation . In addition, computational analyses (AlignGVGD, PolyPhen2, SIFT) do not sugges t a high likelihood of impact to the protein. Arg1084Lys in exon 28 of RYR2 (rs 193922624; allele frequency = n/a)
GeneDx	RCV000171675	SCV000234991	likely benign	not provided	2019-08-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621688	SCV000737629	likely benign	Cardiovascular phenotype	2020-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513261	SCV000822863	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190169	SCV001357595	likely benign	Cardiomyopathy	2019-11-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171675	SCV004126205	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841541	SCV000053088	likely benign	Cardiac arrhythmia	2015-10-02	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157452	SCV000207196	uncertain significance	Primary dilated cardiomyopathy	2014-07-16	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000036727	SCV000280449	uncertain significance	not specified	2011-04-14	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. Arg1084Lys (c.3251G>A) in the RYR2 gene. This variant is novel. It has not been reported in association with disease or as a benign polymorphism. In silico analysis with PolyPhen-2 predicts the variant to be benign. This is a chemically conservative change with a polar positive amino acid replacing another polar positive amino acid. The variant is not conserved across evolution and is in fact a lysine in zebra finch and green puffer. The variant is not listed in dbSNP or 1000 genomes (as of August 2011). Medeiros-Domingo et al (2009) reported that 3% of individuals from the general population carry a rare or novel variant in RYR2. Variants in RYR2 have not been linked to HCM. Other variants in RYR2 have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in this gene have also been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), though this association is debated.