Submissions for variant NM_000540.3(RYR1):c.5036G>A (p.Arg1679His)

gnomAD frequency: 0.00101  dbSNP: rs146504767

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148794	SCV001816154	likely 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 Arginine with Histidine at codon 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, 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 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate.
CSER _CC_NCGL, University of Washington	RCV002051684	SCV000212211	likely benign	Malignant hyperthermia of anesthesia	2015-03-11	criteria provided, single submitter	research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148794	SCV000265706	likely benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000487911	SCV000332292	uncertain significance	not provided	2015-06-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000377673	SCV000412225	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000285430	SCV000412226	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-08-02	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	RCV000342699	SCV000412227	likely benign	Central core myopathy	2018-08-02	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	RCV000148794	SCV000412228	likely benign	Malignant hyperthermia, susceptibility to, 1	2018-08-02	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	RCV000487911	SCV000514424	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19346234, 23919265, 24055113, 25637381, 20142353, 25985138, 26332594, 27153395, 29441698, 24195946, 30611313, 30325262, 31517061, 21965348, 20681998, 22473935)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000382065	SCV000540247	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 5 papers, with comments suggesting VUS in relation to TAAD. It is present in gnomAD with a Max MAF of 0.13% (14/10158 Ashkenazi Jews). It is classified in ClinVar with 2 stars as VUS by Ambry and CSER_CC_NCGL.
CeGaT Center for Human Genetics Tuebingen	RCV000487911	SCV000575172	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RYR1: PP3, BS2
Genetic Services Laboratory, University of Chicago	RCV000382065	SCV000596899	likely benign	not specified	2016-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085867	SCV000659954	likely benign	RYR1-related disorder	2024-01-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000487911	SCV000852666	uncertain significance	not provided	2016-07-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000148794	SCV001141061	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000487911	SCV001715272	uncertain significance	not provided	2020-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000148794	SCV004358080	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-09-23	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148794	SCV000190532	likely benign	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research