Submissions for variant NM_001035.3(RYR2):c.10231-5C>T

gnomAD frequency: 0.00028  dbSNP: rs186326951

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127848	SCV000171430	benign	not specified	2014-02-07	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000127848	SCV000270800	likely benign	not specified	2015-06-10	criteria provided, single submitter	clinical testing	c.10231-5C>T in intron 70 of RYR2: This variant is not expected to have clinica l significance because a C>T change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 0.2% (7/3350) of Latino chromosomes and 0.1% (41/29276) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs186326951).
Invitae	RCV001093730	SCV000285684	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001093730	SCV000356405	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000373146	SCV000356406	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.
Color Diagnostics, LLC DBA Color Health	RCV000777784	SCV000913759	likely benign	Cardiomyopathy	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000127848	SCV002570669	benign	not specified	2022-07-05	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.10231-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00054 in 226606 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia (3.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.10231-5C>T in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as VUS, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002371972	SCV002685330	likely benign	Cardiovascular phenotype	2019-09-12	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705921	SCV003799846	likely benign	not provided	2022-03-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705921	SCV004033018	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RYR2: BP4, BS1
Clinical Genetics, Academic Medical Center	RCV000127848	SCV001920157	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705921	SCV001926328	likely benign	not provided		no assertion criteria provided	clinical testing