19-38457546-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS3_ModeratePS4PP1_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 Leucine at codon 614 of the RYR1 protein, p.(Arg614Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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 (PMID:10051009; PMID:17710899; PMID:10484775 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in seven individuals, PP1_Strong (PMID:9389851; PMID:17710899). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4, PS3_Moderate, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024313/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.1841G>T | p.Arg614Leu | missense_variant | Exon 17 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.1841G>T | p.Arg614Leu | missense_variant | Exon 17 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000599547.6 | n.1841G>T | non_coding_transcript_exon_variant | Exon 17 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
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Reported in the published literature in association with malignant hyperthermia (PMID: 24433488, 16163667, 30236257, 9389851); Published functional studies demonstrate that this variant leads to increased channel sensitivity to caffeine and halothane (PMID: 9334205); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1774074, 28289592, 21795085, 9873004, 26398623, 8602662, 11493496, 31447099, 10352931, 33625594, 11668625, 12411788, 10484775, 9389851, 31206373, 26115329, 24433488, 16163667, 30236257, 31321302, 9334205) -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
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 Leucine at codon 614 of the RYR1 protein, p.(Arg614Leu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in nine unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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 (PMID:10051009; PMID:17710899; PMID:10484775 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in seven individuals, PP1_Strong (PMID:9389851; PMID:17710899). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4, PS3_Moderate, PP1_Strong, PP3_Moderate. -
The c.1841G>T (p.Arg614Leu) variant of the RYR1 gene replaces arginine with leucine at codon 614 of the RYR1 protein (p.Arg614Leu). This missense change has been observed in nine unrelated individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:10051009, 17710899, 10484775, 30236257, 9389851). This variant segregates with malignant hyperthermia (MHS) in seven individuals (PMID:17710899, 9389851). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists (PMID: 27586648, 9873004). Computational prediction (REVEL score 0.931) suggests that this variant may have deleterious impact on protein structure and function. The other alteration affecting the same amino acid, c.1840C>T (p.Arg614Cys), has been classified as pathogenic by the expert panel in ClinVar (ID:12964). For these reasons, the c.1841G>T (p.Arg614Leu) variant of RYR1 is classified as pathogenic. -
RYR1-related disorder Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 614 of the RYR1 protein (p.Arg614Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 9389851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133108). 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 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004). This variant disrupts the p.Arg614 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788). 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. -
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1
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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