Submissions for variant NM_000540.3(RYR1):c.641C>T (p.Thr214Met)

gnomAD frequency: 0.00014  dbSNP: rs727504129

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580430	SCV001810117	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 threonine with methionine at codon 214 of the RYR1 protein, p.(Thr214Met). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00017, a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; all 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) PS4_Moderate (PMID:30236257). This variant has been reported in a fifth individual with a second variant in RYR1 classified as Likely Pathogenic (p.Glu2348del), this individual was not counted toward PS4 (PMID:27857962), the mother of this individual shared the p.Thr214Met variant and was MHN by IVCT, BS2_Moderate. Functional studies in HEK293 cells do not show a significant increase in sensitivity to RYR1 agonists, BS3_Supporting (PMID:27857962). This variant segregates with MHS in three individuals, PP1 (PMID:25658027, PMID:30236257). 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 0.533 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PS4_Moderate, PM1, PP1, BS2_Moderate, BS3_Supporting.
Eurofins Ntd Llc (ga)	RCV000721610	SCV000203446	uncertain significance	not provided	2014-01-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000721610	SCV000852707	uncertain significance	not provided	2013-10-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478448	SCV000896735	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	2021-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815630	SCV000956091	likely benign	RYR1-related disorder	2023-12-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721610	SCV003813147	uncertain significance	not provided	2022-02-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000721610	SCV004021614	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	Observed in patients with malignant hyperthermia susceptibility, however, a second variant was also identified in some of these families that could explain this phenotype (Fiszer et al., 2015; Stephens et al., 2016; Miller et al., 2018; White et al., 2022); Observed with a second RYR1 variant in a patient with congenital myopathy, however, it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes, and the specific testing methodology was not described (Natera-de Benito et al., 2021); Published functional studies did not demonstrate a damaging effect (Stephens et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30236257, 25658027, 33767344, 36208971, 32381029, 33333461, 27857962)
Color Diagnostics, LLC DBA Color Health	RCV003514313	SCV004357267	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 214 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). A functional study in HEK293 cells showed that this variant does not increase sensitivity to RYR1-agonists compared to wild-type RYR1 (PMID: 27857962). This variant has been reported in individuals/families affected with malignant hyperthermia susceptibility (PMID:25658027, 27857962, 30236257, 36208971). One of these individuals also carried a pathogenic variant in the RYR1 gene, which may explain the observed phenotype (PMID: 27857962, 36208971). This variant has been identified in 27/282810 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.
All of Us Research Program, National Institutes of Health	RCV003514313	SCV004820719	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 214 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). A functional study in HEK293 cells showed that this variant does not increase sensitivity to RYR1-agonists compared to wild-type RYR1 (PMID: 27857962). This variant has been reported in individuals/families affected with malignant hyperthermia susceptibility (PMID:25658027, 27857962, 30236257, 36208971). One of these individuals also carried a pathogenic variant in the RYR1 gene, which may explain the observed phenotype (PMID: 27857962, 36208971). This variant has been identified in 27/282810 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000721610	SCV001799409	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000721610	SCV001926569	uncertain significance	not provided		no assertion criteria provided	clinical testing