Submissions for variant NM_001035.3(RYR2):c.10324-4A>G

gnomAD frequency: 0.00203  dbSNP: rs72751287

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036649	SCV000060304	benign	not specified	2013-01-12	criteria provided, single submitter	clinical testing	10324-4A>G in intron 71 of RYR2: This variant is not expected to have clinical s ignificance because it does not affect the splicing consensus sequence and has b een identified in 0.3% (23/6634) of chromosomes from a broad population by the N HGRI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/).
Eurofins Ntd Llc (ga)	RCV000036649	SCV000203487	likely benign	not specified	2014-04-10	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202863	SCV000257746	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2015-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000202863	SCV000285686	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246904	SCV000318758	likely benign	Cardiovascular phenotype	2018-11-27	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.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000036649	SCV000864330	likely benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing	BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768787	SCV000900158	likely benign	Cardiomyopathy	2017-08-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000768787	SCV000910860	benign	Cardiomyopathy	2018-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036649	SCV000920164	benign	not specified	2018-01-22	criteria provided, single submitter	clinical testing	Variant summary: c.10324-4A>G in RYR2 gene is an intronic change that involves a non-conserved nucleotide. 2/5 programs in Alamut predict that this variant creates a new cryptic donor site, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of gnomAD at frequency of 0.00186 (513/275834chrs tested), predominantly in individuals of European (N-F) descent (0.0038;483/ 126018 chrs tested, including 1 homozygote). The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00003, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Benign by reputable database/clinical laboratory. Taking together, the variant was classified as Benign.
Illumina Laboratory Services, Illumina	RCV000202863	SCV001254171	likely benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-03-12	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001097852	SCV001254172	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-03-12	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.
GeneDx	RCV001528231	SCV001893628	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001528231	SCV005330058	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR2: BP4, BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528231	SCV005878411	likely benign	not provided	2024-07-30	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528231	SCV001739610	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036649	SCV001924800	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036649	SCV001928060	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036649	SCV001951736	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528231	SCV001966137	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534774	SCV004731184	benign	RYR2-related disorder	2020-03-09	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).