ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1005+7C>T

gnomAD frequency: 0.00004  dbSNP: rs774100182
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000441658 SCV000530434 likely benign not specified 2016-07-27 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.
Invitae RCV002522429 SCV001706257 likely benign Catecholaminergic polymorphic ventricular tachycardia 1 2022-09-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000441658 SCV002819782 uncertain significance not specified 2023-09-26 criteria provided, single submitter clinical testing Variant summary: RYR2 c.1005+7C>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. Consensus agreement among computation 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 8.2e-06 in 243966 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1005+7C>T has been reported in the literature in at least one individual affected with progressive cardiac conduction disease (e.g., Daumy_2016), however without strong evidence for causality (e.g., lack of co-segregation data). This report therefore does not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 26820365). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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