ClinVar Genomic variation as it relates to human health

p.Arg122Cys (CGC>TGC): c.364 C>T in exon 6 of the RYR2 gene (NM_001035.2). A variant of unknown significance has been identified in the RYR2 gene. The R122C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R122C 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. The R122C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Although missense mutations in nearby residues have not been reported, R122C is located in the N-terminal domain, a mutation hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).

Variant classified as Uncertain Significance - Favor Benign. The Arg122Cys varia nt in RYR2 has not been reported in the literature, but has been identified in 1 individual with CPVT; however, this variant did not segregate with disease in t wo affected family members, suggesting that it may not be primarily responsible for disease in that family. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg122Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although segregation studies suggest th at this variant may be benign and not causing disease in isolation, we cannot ru le out that this variant may be contributing to disease.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the RYR2 protein (p.Arg122Cys). 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 missense change has been observed in individual(s) with autosomal dominant RYR2-related conditions (PMID: 35352813). ClinVar contains an entry for this variant (Variation ID: 43774). 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. This variant disrupts the p.Arg122 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 31112425; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.

This missense variant replaces arginine with cysteine at codon 122 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35352813). This variant has been identified in 4/174666 chromosomes 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.

Variant summary: RYR2 c.364C>T (p.Arg122Cys) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 174666 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.364C>T has been reported in the literature in an individual affected with unexplained cardiac arrest without strong evidence for causality (Grondin_2022). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.364C>T (p.R122C) alteration is located in exon 6 (coding exon 6) of the RYR2 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This missense variant replaces arginine with cysteine at codon 122 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 been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia (PMID: 35352813). This variant has been identified in 4/174666 chromosomes 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.