19-38499997-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PS3_ModeratePS4PP3_ModeratePP1_Strong
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 histidine at codon 2435 of the RYR1 protein, p.(Arg2435His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 26 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 24 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:30236257, 16163667, 21965348, 23842196, 12059893, 17081152, 17710899, 20681998, 31559918, 16732084, 19513315). Functional studies in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205, 27586648). 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 at least 10 families individuals, PP1_Strong (PMID:12059893, 30236257, 32919876). A REVEL score >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024750/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.7304G>A | p.Arg2435His | missense_variant | Exon 45 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.7304G>A | p.Arg2435His | missense_variant | Exon 45 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000594335.5 | n.755G>A | non_coding_transcript_exon_variant | Exon 6 of 49 | 1 | ENSP00000470927.2 | ||||
| RYR1 | ENST00000599547.6 | n.7304G>A | non_coding_transcript_exon_variant | Exon 45 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461798Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727198
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3Other:1
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Published functional studies demonstrate a damaging effect: increased sensitivity to calcium- and halothane-induced intracellular calcium release when compared to the wild type channel (PMID: 11524458); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21157159, 16835904, 9873004, 25256590, 21965348, 9334205, 8220422, 27586648, 28687594, 23842196, 12668474, 33767344, 19648156, 19513315, 30236257, 12124989, 17710899, 9497245, 35428369, 11524458, 32919876) -
Central core myopathy Pathogenic:1Other:1
PS3, PS4, PP3, PM2, PM5 -
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RYR1-related disorder Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2435 of the RYR1 protein (p.Arg2435His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia and/or central core disease (PMID: 8220422, 19658156, 21965348, 23842196). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12966). 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, 11524458, 27586648). For these reasons, this variant has been classified as Pathogenic. -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
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 2435 of the RYR1 protein, p.(Arg2435His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 26 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 24 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: 30236257, 16163667, 21965348, 23842196, 12059893, 17081152, 17710899, 20681998, 31559918, 16732084, 19513315). Functional studies in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 27586648). 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 at least 10 families individuals, PP1_Strong (PMID: 12059893, 30236257, 32919876). A REVEL score >0.85 (0.944) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate. -
Malignant hyperthermia of anesthesia Pathogenic:1
The p.Arg2435His variant in RYR1 has been reported in >15 individuals with malignant hyperthermia and segregated with disease in multiple affected individuals from several families (Riazi 2014, Broman 2011, Carpenter 2009, Zhang 1993, Robinson 2002). This variant was absent from large population studies but has been reported in ClinVar (Variation ID 12966). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Tong 1997, Carpenter 2009, Murayama 2016, Robinson 2002). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1, PP3 -
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