Submissions for variant NM_000540.3(RYR1):c.6742C>T (p.Arg2248Cys)

gnomAD frequency: 0.00001  dbSNP: rs763352221

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001592875	SCV001815837	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 cysteine at codon 2248 of the RYR1 protein, p.(Arg2248Cys). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000231, 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) (PMID:20681998, PMID:30236257). However, the high MAF in the AMR population in gnomAD precludes the use of PS4. 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 0.694 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689155	SCV000816795	uncertain significance	RYR1-related disorder	2022-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2248 of the RYR1 protein (p.Arg2248Cys). This variant is present in population databases (rs763352221, gnomAD 0.02%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 20681998, 25658027). ClinVar contains an entry for this variant (Variation ID: 568713). 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.
GeneDx	RCV001592874	SCV001816955	uncertain significance	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Reported as heterozygous in individuals with malignant hyperthermia; however functional studies of this variant have not been performed to our knowledge (PMID: 30236257, 25658027, 20681998); 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: 16084090, 20681998, 32098966, 25658027, 12668474, 33767344, 30236257)
Revvity Omics, Revvity	RCV001592874	SCV003813166	uncertain significance	not provided	2022-06-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004294	SCV004820894	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2248 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 been reported in two families affected with malignant hyperthermia susceptibility (PMID: 20681998, 25658027). This variant has been identified in 23/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia susceptibility.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702319	SCV005204704	uncertain significance	not specified	2024-06-18	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6742C>T (p.Arg2248Cys) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251104 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Congenital Multicore Myopathy With External Ophthalmoplegia, allowing no conclusion about variant significance. c.6742C>T has been reported in the literature in individuals affected with malignant hyperthermia (Fiszer_2015, Tammaro_2011) and myopathy (Tordjman_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Multicore Myopathy With External Ophthalmoplegia. 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: 25658027, 20681998, 29802573). ClinVar contains an entry for this variant (Variation ID: 568713). Based on the evidence outlined above, the variant was classified as uncertain significance.