Submissions for variant NM_000540.3(RYR1):c.12553G>A (p.Ala4185Thr)

gnomAD frequency: 0.00037  dbSNP: rs151119428

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449977	SCV001653526	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	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 threonine at codon 4185 of the RYR1 protein, p.(Ala4185Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000631, a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three 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: 21455645, 30236257, 31559918, 27555149). 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 <0.5 (0.402) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000209969	SCV000265746	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000376571	SCV000412869	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000286723	SCV000412870	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-11-02	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	RCV000341753	SCV000412871	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000209969	SCV000412872	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-11-02	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	RCV000721276	SCV000590177	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Initially reported in an individual with a positive in-vitro contracture test (IVCT) and suspected malignant hyperthermia susceptibility; however, this individual also harbored an additional RYR1 variant and the contribution of A4185T to the phenotype was uncertain (PMID: 21455645); Subsequently, A4185T was reported as a variant of uncertain significance in an individual who likely had a malignant hyperthermia episode during surgery, but an IVCT was not performed (PMID: 27555149); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27452334, 24195946, 22473935, 32236737, 31559918, 34535181, 21455645, 27555149)
PreventionGenetics, part of Exact Sciences	RCV000721276	SCV000852300	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812854	SCV000953182	likely benign	RYR1-related disorder	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500677	SCV002812222	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-02-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721276	SCV003820575	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000209969	SCV004358208	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-11-16	criteria provided, single submitter	clinical testing