ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3721G>A (p.Val1241Ile) (rs185715460)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768761 SCV000900131 uncertain significance Cardiomyopathy 2016-03-09 criteria provided, single submitter clinical testing
Color RCV000768761 SCV000914068 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the LMM domain of the RYR2 protein that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 44/276948 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724637 SCV000229305 uncertain significance not provided 2015-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000724637 SCV000616959 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The V1241I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It has been observed in another individual referred for ARVC testing at GeneDx in the absence of any disease-causing variants and has also been classified as a variant of uncertain significance in ClinVar by other clinical laboratories (ClinVar SCV000060391.4, SCV000229305.1; Landrum et al., 2016). One clinical laboratory reported non-segregation with disease, as the variant was absent in two affected relatives (ClinVar SCV000060391.4; Landrum et al., 2016). Additionally, an external variant database reports V1241I was observed in 25/66630 (0.04%) alleles from individuals of European (Non-Finnish) background and in 2/8566 (0.02%) alleles from individuals of East Asian background. The V1241I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to valine are tolerated across species, including I1241 in at least one species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, V1241I 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, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign
Invitae RCV000639101 SCV000760662 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1241 of the RYR2 protein (p.Val1241Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs185715460, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 43775). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036736 SCV000060391 likely benign not specified 2018-11-05 criteria provided, single submitter clinical testing The p.Val1241Ile variant in RYR2 is classified as likely benign because it has b een identified in 0.03% (33/128294) of European chromosomes by gnomAD (http://gn omad.broadinstitute.org). Valine (Val) at position 1241 is highly conserved in m ammals and most evolutionarily distant species, though frog and yellowbelly puff erfish carry an isoleucine (Ile; this variant). Additional computational predict ion tools suggest that this variant may not impact the protein. ACMG/AMP Criteri a applied: BS1_Supporting, BP4.

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