Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000658154 | SCV000779925 | uncertain significance | not provided | 2018-05-09 | criteria provided, single submitter | clinical testing | The R4136H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R4136H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants at the same position and in nearby residues have been reported in the Human Gene Mutation Database in individuals with malignant hyperthermia (Stenson et al., 2014). However, the R4136H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Labcorp Genetics |
RCV001239473 | SCV001412349 | uncertain significance | RYR1-related disorder | 2023-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4136 of the RYR1 protein (p.Arg4136His). This variant is present in population databases (rs572373150, gnomAD 0.003%). 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: 546300). 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 RYR1 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. |
| Fulgent Genetics, |
RCV002485495 | SCV002782427 | uncertain significance | Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome | 2021-07-28 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000658154 | SCV003814974 | uncertain significance | not provided | 2021-11-11 | criteria provided, single submitter | clinical testing |