ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6640G>A (p.Val2214Ile) (rs193922795)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV000148822 SCV001810080 uncertain significance Malignant hyperthermia, susceptibility to, 1 2021-08-26 reviewed by expert panel curation This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of valine with isoleucine at codon 2214 of the RYR1 protein, p.Val2214Ile. The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00016, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), however, the high MAF in the AFR population in gnomAD precludes the use of PS4 (PMID:11575529). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.798 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000119666 SCV000230502 uncertain significance not provided 2014-11-15 criteria provided, single submitter clinical testing
Invitae RCV000528915 SCV000660002 pathogenic RYR1-Related Disorders 2020-02-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2214 of the RYR1 protein (p.Val2214Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs193922795, ExAC 0.01%). This variant has been observed in individual(s) with malignant hyperthermia (PMID: 11575529, Invitae). ClinVar contains an entry for this variant (Variation ID: 133168). 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. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119666 SCV000154573 not provided not provided no assertion provided not provided
CSER _CC_NCGL, University of Washington RCV000148822 SCV000190561 uncertain significance Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research

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.