Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001871919 | SCV002146168 | uncertain significance | RYR1-related disorder | 2022-06-20 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 4869 of the RYR1 protein (p.Asp4869Ala). This variant is present in population databases (rs781367427, gnomAD 0.009%). 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: 1048942). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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, |
RCV002476623 | SCV002785913 | 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 | 2021-10-16 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV001354383 | SCV003814483 | uncertain significance | not provided | 2019-07-08 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004005251 | SCV004816271 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with alanine at codon 4869 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 11/251488 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001354383 | SCV001548989 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The RYR1 p.D4869A variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs781367427) and in control databases in 11 of 251488 chromosomes at a frequency of 0.00004374, and was observed at the highest allele count in the European (non-Finnish) population in 7 of 113766 chromosomes (freq: 0.00006153) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.D4869 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |