Submissions for variant NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)

gnomAD frequency: 0.00001  dbSNP: rs118192174

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197410	SCV001368139	pathogenic	Congenital myopathy with fiber type disproportion	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000119694	SCV001747922	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851835	SCV002232164	pathogenic	RYR1-related disorder	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2423 of the RYR1 protein (p.Met2423Lys). This variant is present in population databases (rs118192174, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 17033962, 18253926, 21911697, 30611313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12989). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV001851835	SCV002526405	pathogenic	RYR1-related disorder	2022-06-10	criteria provided, single submitter	clinical testing	The c.7268T>A;p.(Met2423Lys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12989; OMIM: 180901.0027; PMID: 17483490; 17365175; 17033962; 16380615) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (central region) - PM1. The variant is present at low allele frequencies population databases (rs118192174– gnomAD 0.0001987%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 17033962; PMID: 16380615) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Fulgent Genetics, Fulgent Genetics	RCV002504782	SCV002815963	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-10-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119694	SCV003827304	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996094	SCV004820909	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with lysine at codon 2423 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 not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 12989). This variant has been identified in 5/251410 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017243	SCV004847996	likely pathogenic	Neuromuscular disease	2023-11-21	criteria provided, single submitter	clinical testing	The p.Met2423Lys variant in RYR1 has been reported as compound heterozygous in at least 3 individuals with minicore myopathy or Dusty core disease and segregated with disease in 2 affected relatives from 1 family (Jungbluth 2005 PMID: 16380615, Zhou 2006 PMID: 17033962, Zhou 2007 PMID: 17483490, Monnier 2008 PMID: 18253926, Klein 2012 PMID: 21911697, Garibaldi 2019 PMID: 30611313). The p.Met2423Lys variant has also been identified in 0.02% (1/4672) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analysis suggest that the p.Met2423Lys 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.Met2423Lys variant is likely pathogenic for minicore myopathy in an autosomal recessive manner based upon reports of this variant in trans with pathogenic variants and segregation studies. ACMG/AMP criteria applied: PM3_Strong, PP1, PP3.
OMIM	RCV000013861	SCV000034108	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2012-06-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119694	SCV000154601	not provided	not provided		no assertion provided	not provided
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415169	SCV000492579	pathogenic	Clubfoot; EMG abnormality; Lower limb amyotrophy	2016-03-18	no assertion criteria provided	clinical testing