Submissions for variant NM_000540.3(RYR1):c.6670C>T (p.Arg2224Cys)

gnomAD frequency: 0.00007  dbSNP: rs199870223

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000210006	SCV001816145	likely benign	Malignant hyperthermia, susceptibility to, 1	2021-03-18	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 2224 of the RYR1 protein p.(Arg2224Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00091, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in one individual who has a personal or family history of a malignant hyperthermia reaction, this individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257). The high maf in the SAS 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 0.728 supports neither a pathogenic or a benign status. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, PM1.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210006	SCV000265716	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
GeneDx	RCV000521116	SCV000618842	uncertain significance	not provided	2020-02-07	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in an individual with coronary artery disease who did not have any reported history of myopathy or malignant hyperthermia (Gonsalves et al., 2013); 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: 30916033, 26110843, 24195946)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697616	SCV000826237	likely benign	RYR1-related disorder	2024-08-28	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731438	SCV001984028	uncertain significance	not specified	2020-03-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000521116	SCV003815023	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210006	SCV004358104	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2224 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in one family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 41/282330 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.