Submissions for variant NM_000540.3(RYR1):c.4999C>T (p.Arg1667Cys)

gnomAD frequency: 0.00165  dbSNP: rs144157950

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000210024	SCV001816190	benign	Malignant hyperthermia, susceptibility to, 1	2021-03-17	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 1667 of the RYR1 protein, p.(Arg1667Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0051, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000210024	SCV000265705	likely benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238630	SCV000296943	uncertain significance	Malignant hypothermia	2015-11-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000388667	SCV000331847	likely benign	not specified	2015-07-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275346	SCV000412217	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000332661	SCV000412218	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-11-05	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	RCV000371001	SCV000412219	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210024	SCV000412220	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-11-05	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.
GeneDx	RCV000721572	SCV000527243	likely benign	not provided	2020-09-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16732084, 24195946, 21455645, 31517061)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080636	SCV000659951	benign	RYR1-related disorder	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721572	SCV001151845	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	RYR1: BS2
Genetic Services Laboratory, University of Chicago	RCV000388667	SCV002065944	likely benign	not specified	2019-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494548	SCV002798373	likely benign	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000210024	SCV004358079	likely benign	Malignant hyperthermia, susceptibility to, 1	2019-03-29	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000721572	SCV005308614	benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV001080636	SCV000852663	benign	RYR1-related disorder	2020-04-01	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000721572	SCV002034183	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000721572	SCV002036157	likely benign	not provided		no assertion criteria provided	clinical testing