19-38494564-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1_SupportingPS4_ModerateBS2_SupportingPS3_ModeratePM5PP1_StrongPP3_Moderate
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 2163 of the RYR1 protein, p.(Arg2163Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had 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_Moderate (PMID:10484775, PMID:30236257, PMID:9497245). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004). Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID:21118704). This variant segregates with MHS in over 15 individuals PP1_Strong, (PMID:9497245, PMID:30236257, PMID:10484775). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024590/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Publications
- malignant hyperthermia, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
- congenital multicore myopathy with external ophthalmoplegiaInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- RYR1-related myopathyInheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
- central core myopathyInheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
- King-Denborough syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- malignant hyperthermia of anesthesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive centronuclear myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- benign Samaritan congenital myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- congenital myopathy with myasthenic-like onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- lethal multiple pterygium syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR1 | NM_000540.3 | MANE Select | c.6487C>T | p.Arg2163Cys | missense | Exon 39 of 106 | NP_000531.2 | ||
| RYR1 | NM_001042723.2 | c.6487C>T | p.Arg2163Cys | missense | Exon 39 of 105 | NP_001036188.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | TSL:5 MANE Select | c.6487C>T | p.Arg2163Cys | missense | Exon 39 of 106 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | TSL:1 | c.6487C>T | p.Arg2163Cys | missense | Exon 39 of 105 | ENSP00000347667.3 | ||
| RYR1 | ENST00000594335.6 | TSL:1 | n.6487C>T | non_coding_transcript_exon | Exon 39 of 103 | ENSP00000470927.2 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250464 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727192 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Pathogenic:3Other:1
The c.6487C>T (p.Arg2163Cys) variant, located on the exon 39 of the RYR1 gene, replaces arginine with cysteine at codon 2163 of the RYR1 protein (p.Arg2163Cys). This missense change has been observed in 4 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:10484775, 30236257, 9497245). This variant was observed to segregate with malignant hyperthermia (MHS) in more than 15 individuals (PMID:10484775, 30236257, 9497245). To be noted, this variant has been identified in an MH normal individual with a negative IVCT/CHCT result, indicating incomplete penetrance (PMID: 30236257). This missense variant is located in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID:9873004). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. Additionally, an alteration affecting the same amino acid c.6488G>A (p.Arg2163His) was classified as pathogenic by the expert panel (ClinVar ID:12974). For these reasons, the c.6487C>T (p.Arg2163Cys) variant of RYR1 is classified as pathogenic.
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 2163 of the RYR1 protein, p.(Arg2163Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had 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_Moderate (PMID:10484775, PMID:30236257, PMID:9497245). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9873004). Another variant has been assessed as pathogenic at this codon, p.(Arg2163His), PM5 (PMID:30236257 ). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). This variant segregates with MHS in over 15 individuals PP1_Strong, (PMID:9497245, PMID:30236257, PMID:10484775). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate.
This missense variant replaces arginine with cysteine at codon 2163 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this mutant protein is more sensitive to RYR1 agonists than wild type (PMID: 9334205, 9873004, 12732639, 27586648). This variant has been reported in individuals and families affected with malignant hyperthermia (PMID: 9497245, 9497245, 30236257), and it has been shown that this variant segregates with disease in multiple families (PMID: 9497245). This variant has been identified in 3/250464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.6488G>C (p.Arg2163Pro) and c.6488G>A (p.Arg2163His), are considered to be disease-causing (ClinVar variation ID: 133159, 12974), further supporting that this position is important for the protein function. Based on the available evidence, this variant is classified as Pathogenic.
not provided Pathogenic:3Other:1
Published functional studies indicate that R2163C alters channel dynamics by enhancing channel sensitivity compared to wild type (Yang et al., 2003; Murayama et al., 2016); Not observed at a 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: 9334205, 9873004, 12732639, 30236257, 12124989, 12668474, 9497245, 27586648)
Inborn genetic diseases Pathogenic:1
The c.6487C>T (p.R2163C) alteration is located in exon 39 (coding exon 39) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 6487, causing the arginine (R) at amino acid position 2163 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/250464) total alleles studied. The highest observed frequency was 0.016% (1/6130) of Other alleles. This variant was detected as heterozygous in individual(s) with no reported features of malignant hyperthermia susceptibility (Hoppe, 2021; Miller, 2018). This variant was identified in one or more individuals with features consistent with malignant hyperthermia susceptibility and segregated with disease in at least one family (Manning, 1998; Miller, 2018). This amino acid position is highly conserved in available vertebrate species. In an assay testing RYR1 function, this variant showed a functionally abnormal result (Tong, 1997; Yang, 2003; Murayama, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
RYR1-related disorder Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2163 of the RYR1 protein (p.Arg2163Cys). This variant is present in population databases (rs118192175, gnomAD 0.003%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 9497245, 12124989, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12973). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 12732639, 27586648). This variant disrupts the p.Arg2163 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16084090). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Central core myopathy Pathogenic:1
methoxyflurane response - Toxicity Other:1
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
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
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
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
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
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
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