Submissions for variant NM_000540.3(RYR1):c.12884C>T (p.Ala4295Val)

gnomAD frequency: 0.00163  dbSNP: rs193922855

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001132790	SCV001816173	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 Alanine with Valine at codon 4295 of the RYR1 protein, p.(Ala4295Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0019, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited 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 (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), (PMID:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate, (PMID:25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant was observed in cis with a variant assessed as pathogenic, p.(Arg2435His), BP2 (PMID:19513315). A REVEL score <0.5 (0.152) supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, BP2, BP4.
Genetic Services Laboratory, University of Chicago	RCV000119469	SCV000194800	uncertain significance	not provided	2014-05-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000119469	SCV000233217	uncertain significance	not provided	2015-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000119469	SCV000234956	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	Observed in multiple individuals with various RYR1-related clinical features including multminicore disease, malignant hyperthermia susceptibility, central core disease, episodes of rhabdomyolysis, and exertional heat illness; however, each of these individuals harbored additional variants in the RYR1 gene (Jeong et al., 2008; Dlamini et al., 2013; Fiszer et al., 2015); Observed in two symptomatic individuals, but was found to be inherited from asymptomatic parents (Klein et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21157159, 20952238, 25747005, 23628358, 22473935, 25658027, 19513315, 26972305, 27663056, 31559918, 29382405)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529209	SCV000659802	likely benign	RYR1-related disorder	2024-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000119469	SCV000852324	uncertain significance	not provided	2018-02-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119469	SCV001151894	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RYR1: PP3, BS2
Illumina Laboratory Services, Illumina	RCV001132790	SCV001292461	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-06-12	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	RCV001132791	SCV001292462	uncertain significance	Central core myopathy	2018-06-12	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	RCV001132792	SCV001292463	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-06-12	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	RCV001266920	SCV001445101	uncertain significance	Inborn genetic diseases	2015-09-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000119469	SCV001880058	uncertain significance	not provided	2021-01-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000119469	SCV002009087	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119469	SCV003800568	uncertain significance	not provided	2022-04-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000119469	SCV004224634	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	BP4
Breakthrough Genomics, Breakthrough Genomics	RCV000119469	SCV005310893	benign	not provided		criteria provided, single submitter	not provided
Leiden Muscular Dystrophy (RYR1)	RCV000119469	SCV000154376	not provided	not provided		no assertion provided	not provided
GenomeConnect - Invitae Patient Insights Network	RCV001535586	SCV001749584	not provided	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital myopathy with fiber type disproportion; Multiminicore myopathy; Myopathy, RYR1-associated		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-28-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.