ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3163C>T (p.Arg1055Cys)

gnomAD frequency: 0.00002  dbSNP: rs754181384
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523211 SCV000617993 uncertain significance not provided 2021-05-17 criteria provided, single submitter clinical testing Reported in association with hypertrophic cardiomyopathy (HCM) (Lopes et al., 2015); however, no clinical or segregation information was provided; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 449664; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510)
Invitae RCV002527588 SCV000760603 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1055 of the RYR2 protein (p.Arg1055Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 449664). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 RCV001191879 SCV001359801 uncertain significance Cardiomyopathy 2023-02-22 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1055 of 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.
Ambry Genetics RCV002323885 SCV002610116 uncertain significance Cardiovascular phenotype 2020-09-23 criteria provided, single submitter clinical testing The p.R1055C variant (also known as c.3163C>T), located in coding exon 27 of the RYR2 gene, results from a C to T substitution at nucleotide position 3163. The arginine at codon 1055 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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.
Fulgent Genetics, Fulgent Genetics RCV002476056 SCV002781068 uncertain significance Arrhythmogenic right ventricular dysplasia 2; Catecholaminergic polymorphic ventricular tachycardia 1; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome 2021-12-03 criteria provided, single submitter clinical testing

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