ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.2711A>G (p.Tyr904Cys) (rs201131315)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171674 SCV000050700 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156225 SCV000205941 uncertain significance not specified 2013-12-04 criteria provided, single submitter clinical testing The Tyr904Cys variant in RYR2 has not been previously reported in individuals wi th cardiomyopathy but has been identified in 0.1% (2/1500) chromosomes by the Cl inSeq Project (Ng 2013 and dbSNP rs201131315). Computational analyses (amino aci d biochemical properties, conservation, SIFT, AlignGVGD, PolyPhen-2) suggest tha t the Tyr904Cys variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. Additional information is needed to fully assess its clinical significance.
GeneDx RCV000171674 SCV000235081 uncertain significance not provided 2018-07-24 criteria provided, single submitter clinical testing The Y904C variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The Y904C variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y904C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been reported in association with CPVT or RYR2-related arrhythmia and Y904C is not located in any the hotspot regions of the RYR2 gene (Medeiros- Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Ambry Genetics RCV000620905 SCV000734929 uncertain significance Cardiovascular phenotype 2018-08-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000777596 SCV000913461 likely benign Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing
Invitae RCV001088736 SCV001007348 likely benign Catecholaminergic polymorphic ventricular tachycardia 2019-12-31 criteria provided, single submitter clinical testing

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