ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.556G>A (p.Val186Met)

gnomAD frequency: 0.00002  dbSNP: rs201211033
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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 RCV000148834 SCV000050610 uncertain significance Polymorphic ventricular tachycardia 2018-04-05 criteria provided, single submitter research
Invitae RCV002514858 SCV000961212 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-07-11 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 186 of the RYR2 protein (p.Val186Met). This variant is present in population databases (rs201211033, gnomAD 0.007%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). ClinVar contains an entry for this variant (Variation ID: 161382). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV001184735 SCV001350780 uncertain significance Cardiomyopathy 2023-02-28 criteria provided, single submitter clinical testing This variant is located in the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Crystal structure study has suggested that this variant may cause a change in the surface of the protein (PMID: 19913485). This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 16818210). This variant has also been identified in 6/248524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV001762328 SCV002008057 uncertain significance not provided 2021-05-07 criteria provided, single submitter clinical testing Reported in one patient referred for catecholaminergic polymorphic ventricular tachycardia genetic testing (Tester et al., 2006); however, detailed clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 161382; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 32899693, 25637381, 19913485, 24025405, 27538377, 16818210)
Ambry Genetics RCV002345458 SCV002650912 uncertain significance Cardiovascular phenotype 2022-02-26 criteria provided, single submitter clinical testing The p.V186M variant (also known as c.556G>A), located in coding exon 8 of the RYR2 gene, results from a G to A substitution at nucleotide position 556. The valine at codon 186 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in an individual reported to have catecholaminergic polymorphic ventricular tachycardia and possible left ventricular non-compaction (Tester DJ et al. Heart Rhythm, 2006 Jul;3:800-5). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CSER _CC_NCGL, University of Washington RCV000148834 SCV000190575 uncertain significance Polymorphic ventricular tachycardia 2014-06-01 no assertion criteria provided research

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