Submissions for variant NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)

gnomAD frequency: 0.00085  dbSNP: rs147707463

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000210026	SCV001810087	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 serine with phenylalanine at codon 2776 of the RYR1 protein p.(Ser2776Phe). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00145, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. 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 (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), ( PMID:21965348, PMID:30236257 ). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. 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 of 0.693 does not support a pathogenic or a benign status. This variant has been classified as Likely Benign. Criteria implemented: BS1.
Eurofins Ntd Llc (ga)	RCV000721704	SCV000231315	uncertain significance	not provided	2015-04-07	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210026	SCV000265728	likely benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000264650	SCV000412555	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000324517	SCV000412556	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000379118	SCV000412557	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210026	SCV000412558	likely benign	Malignant hyperthermia, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000179118	SCV000540249	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in healthy individuals; ExAC: 0.1% (67/59798) European chromosomes; ClinVar: 1 VUS; ML: Frequent for disease
Athena Diagnostics	RCV000179118	SCV000614916	uncertain significance	not specified	2016-11-04	criteria provided, single submitter	clinical testing
Invitae	RCV001088536	SCV000660061	likely benign	RYR1-related disorder	2024-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001088536	SCV000852832	uncertain significance	RYR1-related disorder	2023-10-13	criteria provided, single submitter	clinical testing	The RYR1 c.8327C>T variant is predicted to result in the amino acid substitution p.Ser2776Phe. This variant was reported in two Malignant Hyperthermia (MH) patients and one patient with King Denborough syndrome (Broman et al. 2011. PubMedID: 21965348; Dowling et al. 2011. PubMedID: 21514828; Gonsalves et al. 2013. PubMedID: 24195946; Fiszer et al. 2015. PubMedID: 25658027). However, the pathogenicity was not clearly established in any of these cases and the asymptomatic mother of the King Denborough patient was heterozygous for the c.8327C>T variant. This suggests the c.8327C>T is less likely to be pathogenic for autosomal dominant RYR1-related disorders, but could be causative for a recessive RYR1-related myopathy. The c.8327C>T variant has been reported in control individuals of European ancestry with an allele frequency of about 0.1% (http://gnomad-old.broadinstitute.org/variant/19-38995965-C-T/). In summary, the clinical significance of the c.8327C>T variant is currently uncertain due to the absence of conclusive evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000721704	SCV000892252	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	RYR1: PP3
GeneDx	RCV000721704	SCV001875161	uncertain significance	not provided	2022-03-18	criteria provided, single submitter	clinical testing	Identified in individuals with RYR1-related neuromuscular disorders; however, in these cases S2776F has been found in conjunction with other potentially pathogenic variants (Fiszer et al., 2015; Snoeck et al., 2015), or as a single variant that was found to be inherited from an unaffected parent (Dowling et al., 2011; Snoeck et al., 2015).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25658027, 21965348, 25960145, 22705209, 27535533, 30788618, 32054689, 24195946, 21514828)
Mayo Clinic Laboratories, Mayo Clinic	RCV000721704	SCV004224631	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210026	SCV004358149	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-07-19	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000210026	SCV004812398	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-05-04	criteria provided, single submitter	clinical testing	European Non-Finnish population allele frequency is 0.1329%% (rs147707463, 186/128,314 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000721704	SCV001932824	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000721704	SCV001952899	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000721704	SCV001972798	likely benign	not provided		no assertion criteria provided	clinical testing