Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000721478 | SCV000620286 | uncertain significance | not provided | 2017-08-23 | criteria provided, single submitter | clinical testing | The R975W variant has been previously reported as a variant of uncertain significance in an individual with central core disease (Brandom et al., 2013). Segregation analysis and comprehensive genetic testing was not completed. The R975W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is where amino acids with similar properties to Arginine are tolerated across species. However, this 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. |
| Invitae | RCV000691361 | SCV000819137 | uncertain significance | RYR1-related disorder | 2024-01-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the RYR1 protein (p.Arg975Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 23558838, 30155738). ClinVar contains an entry for this variant (Variation ID: 451566). 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. |
| Prevention |
RCV000721478 | SCV000852550 | uncertain significance | not provided | 2017-07-20 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002476064 | SCV002783033 | 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 | 2021-11-09 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004003626 | SCV004820791 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2023-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 975 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 autosomal dominant malignant hyperthermia susceptibility in the literature, although it has been reported in individuals affected with other phenotype(s) (ClinVar Variation ID: 451566; PMID: 23558838, 30155738). This variant has been identified in 1/246238 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. |