ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1847C>T (p.Ser616Leu) (rs730880187)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413365 SCV000491117 likely pathogenic not provided 2016-09-08 criteria provided, single submitter clinical testing The S616L variant has been reported previously as de novo in an adolescent female with syncopal spells during exercise, partly ectopic rhythm on ECG and polymorphic ventricular premature complexes on stress test (Marjamaa et al., 2009). This variant has also been found to have apparently occurred de novo in a child tested for arrhythmia at GeneDx; however, maternity and paternity testing was not performed. This variant was absent in 300 blood donors (Marjamaa et al., 2009) and was not observed in approximately 6,200 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 S616L 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, and this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts that S616L is damaging to the structure/function of the protein. However, the S616L variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009).Therefore, this variant is likely pathogenic.
Invitae RCV000685271 SCV000812748 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 616 of the RYR2 protein (p.Ser616Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 19216760, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 180486). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV000157444 SCV000207188 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2014-10-14 no assertion criteria provided clinical testing

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