rs193922860
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM1_Supporting
This summary comes from the ClinGen Evidence Repository: 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 glutamine at codon 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID:16732084). 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_Sup (PMID:21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024086/MONDO:0018493/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.13934G>A | p.Arg4645Gln | missense_variant | 95/106 | ENST00000359596.8 | NP_000531.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.13934G>A | p.Arg4645Gln | missense_variant | 95/106 | 5 | NM_000540.3 | ENSP00000352608 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000987 AC: 15AN: 151986Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251466Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
GnomAD4 exome AF: 0.000251 AC: 367AN: 1461878Hom.: 1 Cov.: 33 AF XY: 0.000241 AC XY: 175AN XY: 727242
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74344
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with glutamine at codon 4645 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 been reported in two individuals who experienced malignant hyperthermia episode, one of whom had another pathogenic variant in the same gene (PMID: 16732084). This variant has been identified in 15/251466 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2020 | Identified as heterozygous in an individual with neuroleptic malignant syndrome, however it was also identified in multiple control samples (Sato et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21918424, 19223216, 16917943, 21878807, 23476141, 19931341, 16732084) - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
RYR1-related disorder Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 07, 2023 | The RYR1 c.13934G>A variant is predicted to result in the amino acid substitution p.Arg4645Gln. This variant has been reported in individuals with malignant hyperthermia (Table S1, Robinson et al. 2006. PubMed ID: 16917943) and in another individual with suspected neuroleptic malignant syndrome (Sato et al. 2010. PubMed ID: 19931341). It was also reported in the compound heterozygous state with another RYR1 variant in an individual who was a victim of heat stroke who was thought to experience stress induced malignant hyperthermia (Nishio et al. 2009. PubMed ID: 19223216; Carsana et al. 2013. PubMed ID: 23476141). This variant was also reported in study of hypermobility spectrum disorder in ballet professionals (Appendix Table A1, Vera et al. 2020. PubMed ID: 31765226:). This variant has also been found in control populations (Sato et al. 2010. PubMed ID: 19931341) and is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39062846-G-A). Of note, this variant has been reviewed by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and was determined to be a variant of uncertain significance for malignant hyperthermia susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/133053/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 12, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4645 of the RYR1 protein (p.Arg4645Gln). This variant is present in population databases (rs193922860, gnomAD 0.04%). This missense change has been observed in individual(s) with neuroleptic malignant syndrome and malignant hyperthermia or suspected malignant hyperthermia (PMID: 16732084, 16917943, 19223216, 19931341). ClinVar contains an entry for this variant (Variation ID: 133053). 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 not 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 paper in HGMD in an unspecified number of malignant hyperthermia patients (classified as DM). This variant is present in ClinVar with no interpretation. The variant has a Max MAF of 0.03% in ExAC (3 East Asian alleles) and 0.04% in gnomAD (7 East Asian alleles). 3 non-mammals have a Gln at this position. - |
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Central core myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Malignant hyperthermia of anesthesia Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Apr 06, 2023 | 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 glutamine at codon 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID: 16732084). 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_Sup (PMID: 21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at