Submissions for variant NM_000540.3(RYR1):c.14524G>A (p.Val4842Met)

gnomAD frequency: 0.00011  dbSNP: rs193922879

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001588937	SCV001815852	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 valine with methionine at codon 4842 of the RYR1 protein, p.(Val4842Met). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.0002, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PP3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546614	SCV000659852	uncertain significance	RYR1-related disorder	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4842 of the RYR1 protein (p.Val4842Met). This variant is present in population databases (rs193922879, gnomAD 0.07%). This missense change has been observed in individual(s) with with autosomal recessive congenital myopathy and an individual affected with malignant hyperthermia susceptibility. In some cases, this variant occurred on the same chromosome as the c.10348–6C>G variant (PMID: 18253926, 20839240, 21062345, 21455645, 23394784, 23553484, 23553787, 26019235, 27854218, 28818389). ClinVar contains an entry for this variant (Variation ID: 133075). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000119524	SCV000701731	uncertain significance	not provided	2017-08-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000616859	SCV000711661	likely pathogenic	Neuromuscular disease	2022-11-03	criteria provided, single submitter	clinical testing	The p.Val4842Met variant in RYR1 has been reported in compound heterozygosity in 13 individuals with centronuclear myopathy (Monneri 2008 PMID: 18253926, Wilmshurst 2010 PMID: 20839240, Bevilacqua 2011 PMID: 21062345). This variant segregated with disease in 3 affected relatives with centronuclear myopathy in 2 families. In the 13 individuals with centronuclear myopathy, the p.Val4842Met variant always occurred in conjunction with the c.10348-6C>G variant on the same copy of the gene (in cis). The p.Val4842Met variant has also been identified in 2/10334 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922879). Computational prediction tools and conservation analysis suggest that the p.Val4842Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val4842Met variant is likely pathogenic for centronuclear myopathy in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3.
CeGaT Center for Human Genetics Tuebingen	RCV000119524	SCV001246312	likely pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001132276	SCV001291931	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-27	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.
Mendelics	RCV002247501	SCV002519298	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498549	SCV002812834	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	2021-09-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119524	SCV003813159	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000546614	SCV004123104	uncertain significance	RYR1-related disorder	2023-07-01	criteria provided, single submitter	research
Athena Diagnostics	RCV000119524	SCV004229924	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Color Diagnostics, LLC DBA Color Health	RCV001132276	SCV004358228	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 4842 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with autosomal dominant malignant hyperthermia (PMID: 21455645). This variant has been associated with other phenotype(s) (ClinVar Variation ID: 133075). This variant has been identified in 21/282634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
All of Us Research Program, National Institutes of Health	RCV001132276	SCV004816269	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 4842 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with autosomal dominant malignant hyperthermia (PMID: 21455645). This variant has been associated with other phenotype(s) (ClinVar Variation ID: 133075). This variant has been identified in 21/282634 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586558	SCV005038500	likely pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2024-03-01	criteria provided, single submitter	research	PM1+PM2+PP2+PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002247501	SCV005185142	uncertain significance	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.14524G>A (p.Val4842Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251266 control chromosomes (gnomAD). c.14524G>A has been reported in the literature in individuals affected with Myopathy, RYR1-Associated (e.g. Monnier_2008, Wilmshurst_2010, Bevilacqua_2011, Zhou_2013, Punetha_2016, Abath Neto_2017, Gonzalez-Quereda_2020), and in many cases it was found in cis with the pathogenic variant c.10348-6C>G. It was also found in an individual with malignant hypothermia susceptibility who had another variant of uncertain significance (Kraeva_2011). These reports do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18253926, 21062345, 23553787, 27854218, 21455645, 32403337, 20839240). ClinVar contains an entry for this variant (Variation ID: 133075). Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Muscular Dystrophy (RYR1)	RCV000119524	SCV000154431	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148830	SCV000190570	uncertain significance	Congenital myopathy with cores	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV000546614	SCV000852424	uncertain significance	RYR1-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The RYR1 c.14524G>A variant is predicted to result in the amino acid substitution p.Val4842Met. This variant, along with the c.10348-6C>G variant on the same allele, has been documented in at least three unrelated families with autosomal recessive RYR1-related congenital myopathy (Monnier et al. 2008. PubMed ID: 18253926; Wilmshurst et al. 2010. PubMed ID: 20839240; Bevilacqua et al. 2011. PubMed ID: 21062345). The c.10348-6C>G variant is predicted to weaken the canonical acceptor splice site at the junction of intron 68 and exon 69 based on available splicing prediction programs (Alamut Visual v2.11). The c.14524G>A (p.Val4842Met) has been classified as a variant of uncertain clinical significance by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133075/). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. While the clinical significance of the c.14524G>A variant by itself is uncertain, we classify this combined haplotype (c.10348-6G>C and c.14524G>A (p.Val4842Met)) as pathogenic.