chr19-38455471-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_StrongPP3_ModeratePM1PS3_ModeratePS4_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 Cysteine at codon 533 of the RYR1 protein, p.(Arg533Cys). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. 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:12709367). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in 8 individuals PP1_Strong (PMID:12709367). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Supporting, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024293/MONDO:0007783/012
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.1597C>T | p.Arg533Cys | missense_variant | 15/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1597C>T | p.Arg533Cys | missense_variant | 15/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1597C>T | p.Arg533Cys | missense_variant | 15/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1597C>T | p.Arg533Cys | missense_variant, NMD_transcript_variant | 15/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461888Hom.: 0 Cov.: 54 AF XY: 0.00000413 AC XY: 3AN XY: 727244
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Oct 12, 2021 | - - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 11, 2020 | - - |
Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces arginine with cysteine at codon 533 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). Functional studies have shown that this variant increases sensitivity to RYR1 agonist 4-chloro-m-cresol (PMID: 23459219). This variant has been reported in an individual affected with malignant hyperthermia and has been shown to segregate with disease in eight additional family members (PMID: 12709367). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Mar 17, 2021 | 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 Cysteine at codon 533 of the RYR1 protein, p.(Arg533Cys). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. 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:12709367). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 8 individuals PP1_Strong (PMID:12709367). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Supporting, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate. - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 533 of the RYR1 protein (p.Arg533Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 12709367). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133102). 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%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23459219). This variant disrupts the p.Arg533 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 20681998), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
methoxyflurane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
sevoflurane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
isoflurane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
enflurane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
halothane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
desflurane response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
succinylcholine response - Toxicity Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at