Submissions for variant NM_001035.3(RYR2):c.9067+12C>T

gnomAD frequency: 0.00143  dbSNP: rs112365440

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036802	SCV000060457	benign	not specified	2017-08-31	criteria provided, single submitter	clinical testing	c.9067+12C>T in intron 63 of RYR2: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.3% (66/25344) of Finnish chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112365440).
Illumina Laboratory Services, Illumina	RCV001101435	SCV001258040	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-05-15	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.
Illumina Laboratory Services, Illumina	RCV001101436	SCV001258041	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2018-05-15	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036802	SCV001623439	benign	not specified	2021-05-17	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.9067+12C>T alters a 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 0.0015 in 239310 control chromosomes. The observed variant frequency is approximately 43- fold the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.9067+12C>T has been reported in the literature in at least one individual affected with dilated cardiomyopathy (DCM, Pugh_2014). This report does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. Co-occurrences with other pathogenic/ likely pathogenic variants have been reported (TTN c.69717_69718insC, p.Ser23240GlnfsX19,Pugh_2014 and KCNQ1 c.153C>G,p.Tyr51X, internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001529841	SCV001911347	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001101436	SCV002373676	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2025-02-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529841	SCV004564951	benign	not provided	2023-12-26	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529841	SCV001744016	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036802	SCV001922796	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036802	SCV001928078	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036802	SCV001951845	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529841	SCV001974407	likely benign	not provided		no assertion criteria provided	clinical testing