Submissions for variant NM_000540.3(RYR1):c.5183C>T (p.Ser1728Phe)

gnomAD frequency: 0.00001  dbSNP: rs193922781

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148807	SCV003930277	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-05-20	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 Serine with Phenylalanine at codon 1728 of the RYR1 protein, p.(Ser1728Phe). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: MAF 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, nine 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 (PMID:30236257; PMID:15731587). This variant segregates with MHS in five families, PP1_Strong (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 <0.5 supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PP1_Strong, BP4.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148807	SCV000265707	pathogenic	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001057054	SCV001221528	likely pathogenic	RYR1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1728 of the RYR1 protein (p.Ser1728Phe). This variant is present in population databases (rs193922781, gnomAD 0.003%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 16917943, 19648156, 30236257, 31559918). ClinVar contains an entry for this variant (Variation ID: 133144). 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 not expected to disrupt RYR1 protein function with a negative predictive value of 95%. This variant disrupts the p.Ser1728 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 15731587), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000148807	SCV001439388	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2020-09-03	criteria provided, single submitter	research	ACMG codes:PS4, PM2, PP3, PP5
Ambry Genetics	RCV001265978	SCV001444150	likely pathogenic	Inborn genetic diseases	2016-08-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449805	SCV001653097	likely pathogenic	Malignant hyperthermia of anesthesia	2020-02-11	criteria provided, single submitter	clinical testing	The p.Ser1728Phe variant in RYR1 has been reported in at least 8 individuals with malignant hyperthermia susceptibility (MH) and segregated with disease in 6 affected family members (Robinson 2006 PMID:16917943, Dalton 2007 (thesis), Carpenter 2009 PMID 19648156, Miller 2018 PMID 30236257). In one family, it was reported not to segregate clearly with disease (with phenotyping based on in vitro contracture tests; IVCT) but no specific details were provided (Miller 2018 PMID 30236257). In addition, it has been reported at least 1 individual with no personal or family history of MH (Gonsalves 2013 PMID 24195946), was identified in 1/34500 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has also been reported in ClinVar (Variation ID 133144). Notably, IVCT performed on muscle tissue from individuals carrying this variant suggest that the p.Ser1728Phe variant may be associated with weaker MH phenotypes (Carpenter 2009 PMID 19648156). Computational prediction tools and conservation analysis suggest that the variant may not impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MH with a less severe phenotype than other disease causing RYR1 variants. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Moderate, PS3_Moderate, BP4.
GeneDx	RCV000119633	SCV001819991	likely pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with malignant hyperthermia (MH) in published literature (PMID: 16917943, 30236257, 19648156); Reported in multiple affected individuals from two families with MH; the S1728F variant was associated with a weaker IVCT phenotype compared to other known pathogenic variants in RYR1, suggesting a lesser effect on channel function (PMID: 19648156); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 15731587, 24195946, 20566647, 16917943, 30236257, 31559918, 30916033, 34930662, 37787745, 19648156, 38295319, 38542460)
Revvity Omics, Revvity	RCV000119633	SCV002019098	likely pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000148807	SCV002522189	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-08-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505055	SCV002815271	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-10-22	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000148807	SCV004046154	likely pathogenic	Malignant hyperthermia, susceptibility to, 1		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with malignant hyperthermia (MH) susceptibility (PMID: 19648156, 30236257). In vitro contracture tests have shown this variant may be associated with a weaker MH phenotype (PMID: 19648156). The c.5183C>T (p.Ser1728Phe) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/246040) and is absent in the homozygous state, thus is presumed to be rare. The c.5183C>T (p.Ser1728Phe) variant affects a moderately conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.5183C>T (p.Ser1728Phe) variant is classified as Likely Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119633	SCV000154540	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148807	SCV000190546	pathogenic	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001057054	SCV000852674	likely pathogenic	RYR1-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The RYR1 c.5183C>T variant is predicted to result in the amino acid substitution p.Ser1728Phe. This variant has been reported to be causative for malignant hyperthermia (MH) in several patients (Robinson et al. 2006. PubMed ID: 16917943; Carpenter et al. 2009. PubMed ID: 19648156). We have also observed this variant in two additional patients at PreventionGenetics (internal data). This variant has been interpreted as likely pathogenic by the the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133144/). A different substitution at the same amino acid (p.Ser1728Pro) has also been reported to be causative for RYR1-related disorders (Sambuughin et al. 2005. PubMed ID: 15731587). In summary, the c.5183C>T (p.Ser1728Phe) variant is categorized as likely pathogenic.