ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6532G>A (p.Val2178Ile) (rs794728821)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182874 SCV000235262 uncertain significance not provided 2016-04-14 criteria provided, single submitter clinical testing The Val2178Ile variant in the RYR2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Val2178Ile is a conservative amino acid substitution of a non-polar Valine with a non-polar Isoleucine at a position that is conserved through mammals. The NHLBI ESP Exome Variant Server reports Val2178Ile was not observed in approximately 4,900 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations; however, ethnically-matched control data is not available for this variant. In addition, Val2178 is not located in any of the mutation hotspot regions of the RYR2 gene (Medeiros-Domingo A et al., 2009). With the clinical and molecular information available at this time, we cannot determine whether Val2178Ile in the RYR2 gene is a disease-causing mutation or a benign variant.
Invitae RCV001217364 SCV001389200 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2178 of the RYR2 protein (p.Val2178Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual who suffered sudden cardiac death (PMID: 22787013). ClinVar contains an entry for this variant (Variation ID: 201385). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253231 SCV001428848 likely pathogenic Arrhythmogenic right ventricular dysplasia, familial, 2 2018-10-15 criteria provided, single submitter clinical testing

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