Submissions for variant NM_000540.3(RYR1):c.3523G>A (p.Glu1175Lys)

gnomAD frequency: 0.00001  dbSNP: rs769744438

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655600	SCV000777531	pathogenic	RYR1-related disorder	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1175 of the RYR1 protein (p.Glu1175Lys). This variant is present in population databases (rs769744438, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 25214167, 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant congenital myopathy (PMID: 25635128; internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 544453). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000721499	SCV001449674	likely pathogenic	not provided	2017-02-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004155	SCV004820813	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1175 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 phenotypes (ClinVar Variation ID: 544453). This variant has been identified in 7/282856 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	RCV004586854	SCV005038484	likely pathogenic	Centronuclear myopathy	2024-03-01	criteria provided, single submitter	research	PM3_Strong+PM2+PP1+PP2
Fulgent Genetics, Fulgent Genetics	RCV005019092	SCV005647460	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000655600	SCV000852576	pathogenic	RYR1-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The RYR1 c.3523G>A variant is predicted to result in the amino acid substitution p.Glu1175Lys. The RYR1 gene variant c.3523G>A is predicted to result in the amino acid substitution p.Glu1175Lys. The c.3523G>A variant has been reported in the compound heterozygous state in many individuals with autosomal recessive RYR1 myopathy (Abath Neto et al 2017. PubMed ID: 28818389; Savarese et al. 2014. PubMed ID: 25214167; Ng, G.H.T., et al. 2017. Hong Kong Journal of Radiology; Chae et al. 2015. PubMed ID: 25635128). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic for autosomal recessive RYR1 myopathy.