Submissions for variant NM_000540.3(RYR1):c.14209C>T (p.Arg4737Trp)

gnomAD frequency: 0.00001  dbSNP: rs193922867

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449998	SCV001653548	likely pathogenic	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 tryptophan at codon 4737 of the RYR1 protein, p.(Arg4737Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five individuals 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), PS4_Moderate (PMID: 16163667, 26631338, 30236257, VCEP participating clinical laboratory). This variant segregates with MHS in 4 individuals, PP1 (PMID:26631338, 12208234). 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_Sup (PMID: 21118704). A REVEL score >0.85 (.882) supports a pathogenic status for this variant, PP3_Moderate. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4737Gln), PM5_Supporting (PMID: 23460944). This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_moderate.
PreventionGenetics, part of Exact Sciences	RCV000119502	SCV000852397	pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070022	SCV001235229	pathogenic	RYR1-related disorder	2024-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4737 of the RYR1 protein (p.Arg4737Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 12208234, 16163667, 26631338). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg4736Trp. ClinVar contains an entry for this variant (Variation ID: 133060). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). This variant disrupts the p.Arg4737 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16163667, 18564801, 19648156, 25960145). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000119502	SCV001875125	pathogenic	not provided	2021-07-12	criteria provided, single submitter	clinical testing	Published functional analysis showed that R4737W increases the probability of the channel opening, resulting in calcium leak and disrupting channel function relative to controls (Kushnir et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 12208234, 16163667, 25960145, 32236737, 20566647, 16835904, 31130284, 27558158, 26631338)
Revvity Omics, Revvity	RCV000119502	SCV002019923	pathogenic	not provided	2019-01-03	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004820832	SCV005442164	pathogenic	Central core myopathy	2024-12-19	criteria provided, single submitter	clinical testing
Suma Genomics	RCV001070022	SCV005888635	pathogenic	RYR1-related disorder		criteria provided, single submitter	clinical testing	A missense variant c.14209C>T, p.(Arg4737Trp) is observed in exon 98 of RYR1 in homozygous state. This variant is reported in the ClinVar database as likely pathogenic (ClinVar id. 133060) and also curated by the ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel (Johnston et al. 2022). In-silico analysis tool REVEL is consistent in predicting this variant to be disease-causing. ACMG classification: Pathogenic Criteria met: PS4_Moderate PM1_Supporting PM5_Supporting PP1 PP3
RYR1 database	RCV000119502	SCV000154409	not provided	not provided		no assertion provided	not provided