ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12492G>A (p.Gln4164=) (rs377293019)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182645 SCV000235020 benign not specified 2014-10-03 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 RCV000458228 SCV000554611 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620224 SCV000735613 likely benign Cardiovascular phenotype 2016-11-10 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Color RCV000771837 SCV000904550 likely benign Cardiomyopathy 2018-06-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000182645 SCV000920168 benign not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: RYR2 c.12492G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 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 0.0002 in 276742 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.12492G>A, has been reported in the literature in one individual affected with Cardiomyopathy as a benign variant (Berge_2008). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001099829 SCV001256317 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-17 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.
Illumina Clinical Services Laboratory,Illumina RCV001099830 SCV001256318 benign Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-15 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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