Submissions for variant NM_000540.3(RYR1):c.2996G>A (p.Arg999His)

gnomAD frequency: 0.00005  dbSNP: rs180714609

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000307345	SCV001816153	uncertain significance	Malignant hyperthermia, susceptibility to, 1	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 Arginine with Histidine at codon 999 of the RYR1 protein, p.(Arg999His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00012, a frequency consistent with pathogenicity for MHS. This variant has been reported in two siblings with central core disease and multi-minicore disease (PMID:16372898). A functional study using patient lymphoblasts was published for this variant, this ex vivo assay did not show a significant shift in the EC50 for calcium release in response to RYR1 agonist as compared to wildtype lymphoblasts (PMID:16372898). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.817 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria were implemented.
Eurofins Ntd Llc (ga)	RCV000119605	SCV000345535	uncertain significance	not provided	2016-09-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000310667	SCV000412003	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346959	SCV000412004	likely benign	Congenital multicore myopathy with external ophthalmoplegia	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). 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.
Illumina Laboratory Services, Illumina	RCV000391226	SCV000412005	likely benign	Central core myopathy	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000307345	SCV000412006	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000119605	SCV000620280	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in a patient with multi-minicore disease; this variant was also present in a mildly affected sibling and their unaffected mother (Ducreux et al., 2006); In vitro analysis of R999H indicates that this variant does not affect the intracellular Ca2+ release or sensitivity of the receptor to 4-cmc (Ducreux et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32381029, 16372898)
PreventionGenetics, part of Exact Sciences	RCV000119605	SCV000852556	uncertain significance	not provided	2013-10-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822159	SCV000962949	uncertain significance	RYR1-related disorder	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 999 of the RYR1 protein (p.Arg999His). This variant is present in population databases (rs180714609, gnomAD 0.01%). This missense change has been observed in individual(s) with multiminicore disease (PMID: 16372898). ClinVar contains an entry for this variant (Variation ID: 133122). 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. Experimental studies have shown that this missense change does not substantially affect RYR1 function (PMID: 16372898). 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.
Baylor Genetics	RCV000391226	SCV001524894	uncertain significance	Central core myopathy	2019-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002492408	SCV002777545	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	2021-09-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000391226	SCV004807428	uncertain significance	Central core myopathy	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000307345	SCV004820795	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 999 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). A functional study using patient-derived lymphoblasts showed cells carrying this variant did not have increased sensitivity to RYR1-agonists compared to cells carrying wild-type RYR1 (PMID: 16372898). This variant has been identified in a siblings affected with multi-minicores disease and central core disease (PMID: 16372898). This variant has been identified in 17/249292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (RYR1)	RCV000119605	SCV000154512	not provided	not provided		no assertion provided	not provided