ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.10258G>A (p.Val3420Ile) (rs397516497)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036648 SCV000060303 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing The p.Val3420Ile variant in RYR2 has been identified in 1 individual with arrhyt hmia and sudden cardiac arrest who carried an additional variant of uncertain si gnificance in RYR2 (LMM data). It has also been identified in 0.02% (5/29082) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computati onal prediction tools and conservation analysis suggest that this variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Val3420Ile variant is uncertain. ACMG/AMP Criteria applied: PP3.
GeneDx RCV000766724 SCV000235169 uncertain significance not provided 2013-07-05 criteria provided, single submitter clinical testing p.Val3420Ile (GTT>ATT): c.10258 G>A in exon 71 of the RYR2 gene (NM_001035.2). The Val3420Ile variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val3420Ile results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Val3420Ile is probably damaging to the protein structure/function. The Val3420Ile 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. Nevertheless, Val3420Ile is not located in a mutation hot spot" domain and no mutations in nearby codons have been reported in association with CPVT, indicating this region of the protein may be tolerant of change. We cannot definitively determine if Val3420Ile is a disease-causing mutation or a rare benign variant. The variant is found in CPVT panel(s)."
Invitae RCV000816216 SCV000956713 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 3420 of the RYR2 protein (p.Val3420Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs397516497, ExAC 0.03%). This variant has not been reported in the literature in individuals with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 43697). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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