ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.3164G>A (p.Arg1055His) (rs757490010)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182710 SCV000235090 uncertain significance not specified 2014-08-27 criteria provided, single submitter clinical testing p.Arg1055His (CGC>CAC): c.3164 G>A in exon 27 of the RYR2 gene (NM_001035.2). The R1055H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1055H variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved among mammals. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1055H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, only one missense mutation in a nearby residue (R1051P) has been reported in association with CPVT, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000696774 SCV000825351 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-03-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1055 of the RYR2 protein (p.Arg1055His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs757490010, ExAC 0.03%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201236). 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.
Illumina Clinical Services Laboratory,Illumina RCV001097098 SCV001253350 uncertain significance Catecholaminergic polymorphic ventricular tachycardia type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001097099 SCV001253351 uncertain significance Arrhythmogenic right ventricular dysplasia, familial, 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color RCV001186489 SCV001352925 uncertain significance Cardiomyopathy 2019-03-16 criteria provided, single submitter clinical testing

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