Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000699143 | SCV000827841 | uncertain significance | RYR1-related disorder | 2024-05-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2183 of the RYR1 protein (p.Gly2183Arg). This variant is present in population databases (rs774275648, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576609). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| Prevention |
RCV000721615 | SCV000852716 | uncertain significance | not provided | 2015-05-05 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000721615 | SCV003813145 | uncertain significance | not provided | 2023-04-13 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003999689 | SCV004815077 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2024-09-23 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 2183 of the RYR1 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 13/249232 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702343 | SCV005203041 | uncertain significance | not specified | 2024-07-22 | criteria provided, single submitter | clinical testing | Variant summary: RYR1 c.6547G>A (p.Gly2183Arg) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-05 in 249232 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated, allowing no conclusion about variant significance. c.6547G>A has been reported in the literature in individuals affected with Myopathy, RYR1-Associated (Kushnir_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32236737). ClinVar contains an entry for this variant (Variation ID: 576609). Based on the evidence outlined above, the variant was classified as uncertain significance. |