Submissions for variant NM_000540.3(RYR1):c.12881C>T (p.Thr4294Met)

gnomAD frequency: 0.00471  dbSNP: rs587784372

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001131812	SCV001816193	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 Threonine with Methionine at codon 4294 of the RYR1 protein, p.(Thr4294Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0193, 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.
Genetic Services Laboratory, University of Chicago	RCV000147411	SCV000194799	uncertain significance	not provided	2014-01-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000147411	SCV000340017	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000147411	SCV000617752	benign	not provided	2020-07-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19807743, 23476141, 28326467, 27663056)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085481	SCV000659801	likely benign	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001131811	SCV001291448	uncertain significance	Central core myopathy	2019-01-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001131812	SCV001291449	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2019-01-28	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001131813	SCV001291450	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2019-01-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV001266698	SCV001444875	uncertain significance	Inborn genetic diseases	2016-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498669	SCV002809298	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	2022-04-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000147411	SCV004701663	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	RYR1: PP3, BS1
PreventionGenetics, part of Exact Sciences	RCV001085481	SCV000852323	likely benign	RYR1-related disorder	2023-04-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).