chr19-38440830-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM5PP2PP3_ModeratePP5_Strong
The NM_000540.3(RYR1):c.131G>A(p.Arg44His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,611,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.131G>A | p.Arg44His | missense_variant | 2/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.131G>A | p.Arg44His | missense_variant | 2/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.131G>A | p.Arg44His | missense_variant | 2/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.131G>A | p.Arg44His | missense_variant, NMD_transcript_variant | 2/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 242016Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131980
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1458888Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 725622
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 19, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2021 | Reported in association with malignant hyperthermia (Robinson et al., 2006; Galli et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20301325, 16917943, 25637381, 16835904) - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Apr 07, 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 histidine at codon 44 of the RYR1 protein, p.(Arg44His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000066, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257 ). 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, (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This missense variant replaces arginine with histidine at codon 44 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). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in three individuals affected with malignant hyperthermia susceptibility or with a history of a malignant hyperthermia event (PMID: 16835904, 16917943, 30236257, ClinVar: SCV000659808.3). This variant has been identified in 3/242016 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.130C>T (p.Arg44Cys), is considered pathogenic (ClinVar Variation ID: 133045), indicating that Arg at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Central core disease, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 30, 2017 | This variant has previously been reported in the literature and by clinical laboratories in ClinVar as pathogenic or likely pathogenic (PMID: 16917943, 16835904) (ClinVar Variation ID 133046). There p.Arg44His variant has not been functionally characterized, but a different amino acid substitution at the same position (p.Arg44Cys) has functional evidence supporting the damaging effect on protein function (PMID: 23422674, 23459219, 12709367). RYR1 is missense intolerant, and in silico models predict the variant to be deleterious. The variant occurs at a highly conserved residue among vertebrates. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/242016) and thus is presumed to be rare. Based on the combined evidence, the variant is classified as pathogenic. - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 44 of the RYR1 protein (p.Arg44His). This variant is present in population databases (rs139161723, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (PMID: 16835904, 16917943; Invitae). This variant has been reported in individual(s) with autosomal recessive congenital myopathy (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 133046). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 05, 2017 | - - |
Malignant hyperthermia of anesthesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2018 | The p.Arg44His variant in RYR1 has been reported in 2 European individuals with malignant hyperthermia (MH; Galli 2006, Robinson 2006). This variant has been identified in 1/14292 African chromosomes and in 2/106944 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139161723). This frequency is consistent with the frequency of MH in the general population. Computational prediction tools and conservation analysis suggest that the p.Arg44His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg44His variant is uncertain. ACMG/AMP Criteria applied (Richards 2015): PM2; PP3; PS4_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at