Submissions for variant NM_000540.3(RYR1):c.7778G>A (p.Arg2593His)

gnomAD frequency: 0.00002  dbSNP: rs751180702

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001803989	SCV002047618	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	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 arginine with histidine at codon 2593 of the RYR1 protein, p.(Arg2593His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000349, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had 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, one individual had a second variant of uncertain significance in RYR1 (p.Arg401Leu) and was not considered for PS4, PS4_Supporting (PMID:17968765, PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.825 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810024	SCV000950210	uncertain significance	RYR1-related disorder	2022-10-17	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 2593 of the RYR1 protein (p.Arg2593His). This variant is present in population databases (rs751180702, gnomAD 0.005%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 17968765). ClinVar contains an entry for this variant (Variation ID: 654130). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001706709	SCV001934553	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2020-09-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002495116	SCV002800750	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	2021-10-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003132072	SCV003813086	uncertain significance	not provided	2019-08-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586936	SCV005077478	uncertain significance	not specified	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.7778G>A (p.Arg2593His) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7778G>A has been reported in the literature in two individuals affected with Malignant Hyperthermia (MH) Susceptibility or a family history of MH, in one of those patients, a second heterozygous missense was also reported (p.Arg401Leu, Likely Pathogenic in ClinVar) (Adam_2007, Miller_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30236257, 17968765). ClinVar contains an entry for this variant (Variation ID: 654130). Based on the evidence outlined above, the variant was classified as uncertain significance.