Submissions for variant NM_000540.3(RYR1):c.13691G>A (p.Arg4564Gln)

gnomAD frequency: 0.00003  dbSNP: rs864309559

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202927	SCV000257712	uncertain significance	Malignant hypothermia	2015-06-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208078	SCV001379450	pathogenic	RYR1-related disorder	2024-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4564 of the RYR1 protein (p.Arg4564Gln). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related conditions (PMID: 18253926, 30611313, 33333461; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.13676G>A. ClinVar contains an entry for this variant (Variation ID: 218466). 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 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001563060	SCV001785936	likely pathogenic	not provided	2024-07-06	criteria provided, single submitter	clinical testing	Identified with additional variants in the RYR1 gene in individuals with central core disease, multiminicore disease, and congenital myopathy in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 30611313, 35693006, 33333461, 35428369); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33333461, 30611313, 35428369, 35693006)
Pediatric Department, Peking University First Hospital	RCV001828041	SCV002097048	likely pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2022-02-08	criteria provided, single submitter	provider interpretation
Revvity Omics, Revvity	RCV001563060	SCV003813109	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147404	SCV003836413	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001208078	SCV003853282	likely pathogenic	RYR1-related disorder		criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003147404	SCV004816245	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-01	flagged submission	clinical testing	This missense variant replaces arginine with glutamine at codon 4564 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: 218466; PMID: 18253926, 30611313, 33333461). This variant has been identified in 2/282866 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.