ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14717C>G (p.Ala4906Gly)

gnomAD frequency: 0.00003  dbSNP: rs118192153
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000173935 SCV000225116 uncertain significance not provided 2014-12-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000797894 SCV000937480 uncertain significance RYR1-related disorder 2022-08-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 4906 of the RYR1 protein (p.Ala4906Gly). This variant is present in population databases (rs118192153, gnomAD 0.002%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 23558838). ClinVar contains an entry for this variant (Variation ID: 193772). 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 not expected to disrupt RYR1 protein function. This variant disrupts the p.Ala4906 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11741831, 12642598, 30611313). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, Fulgent Genetics RCV002485122 SCV002791933 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 2021-10-11 criteria provided, single submitter clinical testing
GeneDx RCV000173935 SCV004034743 uncertain significance not provided 2023-03-01 criteria provided, single submitter clinical testing Reported in the sibling of a proband who died from apparent malignant hyperthermia; however, no clinical information was provided for the sibling (Brandom et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23558838, 20681998)

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.