Submissions for variant NM_000540.3(RYR1):c.2797G>A (p.Ala933Thr)

gnomAD frequency: 0.00137  dbSNP: rs148623597

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000990197	SCV001816189	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 Alanine with Threonine at codon 933 of the RYR1 protein, p.(Ala933Thr). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00388, 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.
Illumina Laboratory Services, Illumina	RCV000398721	SCV000411962	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000721476	SCV000577351	likely benign	not provided	2021-03-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 25637381, 19807743, 23476141, 27663056, 28326467)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081561	SCV000777608	likely benign	RYR1-related disorder	2025-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000990197	SCV001141056	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125804	SCV001284916	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000990197	SCV001284917	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000990197	SCV004357296	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-08-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000990197	SCV005430919	likely benign	Malignant hyperthermia, susceptibility to, 1	2024-09-23	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148792	SCV000190530	likely benign	Malignant hyperthermia and exertional rhabdomyolosis	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001081561	SCV000852547	likely benign	RYR1-related disorder	2021-08-25	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).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000721476	SCV001808748	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000721476	SCV001956017	uncertain significance	not provided		no assertion criteria provided	clinical testing