19-38451842-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5PP1PS3_ModeratePS4_ModeratePM1_SupportingPP3_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 401 of the RYR1 protein p.(Arg401Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate ( PMID:30236257, PMID:12434264, PMID:24433488, PMID:25735680). This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate, (PMID:23459219). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5 (PMID:16917943). 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). A REVEL score > 0.85 (0.886) supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023956/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR1 | ENST00000359596.8 | c.1201C>T | p.Arg401Cys | missense_variant | Exon 12 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
| RYR1 | ENST00000355481.8 | c.1201C>T | p.Arg401Cys | missense_variant | Exon 12 of 105 | 1 | ENSP00000347667.3 | |||
| RYR1 | ENST00000599547.6 | n.1201C>T | non_coding_transcript_exon_variant | Exon 12 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727244
GnomAD4 genome 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
not provided Pathogenic:4Other:1
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RYR1: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP1 -
In addition to malignant hyperthermia susceptibility, some individuals who harbored the R401C variant presented with additional neuromuscular features including muscle cramps, multicore/minicore myopathy, and elevated CK levels (Davis et al., 2002; Galli et al., 2002); Functional analysis of R401C shows that it leads to higher sensitivity to agonist compared to wildtype controls (Sato et al., 2013); 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: 30236257, 28326467, 14999498, 32381029, 25735680, 23459219, 23919265, 29635721, 24433488, 16917943, 28818389, 12208234, 18564801, 12434264, 23553484, 12066726, 31589614) -
Malignant hyperthermia, susceptibility to, 1 Pathogenic:4
_x000D_ Criteria applied: PS3, PS4_MOD, PM1, PM5_STR, PM2_SUP, PP1, PP3 -
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 401 of the RYR1 protein p.(Arg401Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate ( PMID:30236257, PMID:12434264, PMID:24433488, PMID:25735680). This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate, (PMID:23459219). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5 (PMID:16917943). 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). A REVEL score > 0.85 (0.886) supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). -
This missense variant replaces arginine with cysteine at codon 401 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 4-CmC and caffeine compare to wild-type RYR1 in HEK293 cells (PMID: 23459219, 26115329, 31841587). This variant has been reported in at least 4 individuals affected with malignant hyperthermia clinical crises and in at least 4 families affected with malignant hyperthermia susceptibility (PMID: 12066726, 12066726, 12434264, 18564801, 24433488, 25735680, 30236257). It has been shown that this variant segregates with disease in two families (PMID: 12066726). This variant has been identified in 2/282746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
This missense variant replaces arginine with cysteine at codon 401 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 4-CmC and caffeine compare to wild-type RYR1 in HEK293 cells (PMID: 23459219, 26115329, 31841587). This variant has been reported in at least 4 individuals affected with malignant hyperthermia clinical crises and in at least 4 families affected with malignant hyperthermia susceptibility (PMID: 12066726, 12066726, 12434264, 18564801, 24433488, 25735680, 30236257). It has been shown that this variant segregates with disease in two families (PMID: 12066726). This variant has been identified in 2/282746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
RYR1-related disorder Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the RYR1 protein (p.Arg401Cys). This variant is present in population databases (rs193922764, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia susceptibility and/or autosomal recessive RYR1-related myopathy (PMID: 12066726, 23919265, 24433488, 25735680, 28818389, 30236257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133029). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23459219). This variant disrupts the p.Arg401 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12059893, 24433488; internal data). 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. -
The RYR1 c.1201C>T variant is predicted to result in the amino acid substitution p.Arg401Cys. This variant has been reported to be causative for Malignant Hyperthermia (MH) in multiple families (Davis et al. 2002. PubMed ID: 12066726; Robinson et al. 2006. PubMed ID: 16917943; Gillies et al. 2015. PubMed ID: 25735680; Miller et al. 2018. PubMed ID: 30236257). Functional studies in transfected cell cultures indicate that the p.Arg401Cys variant results in Ca++ channels that are more sensitive to triggering agents than wild type channels (Sato K. et al. 2013. PubMed ID: 23459219). Several other substitutions at the same amino acid (p.Arg401Gly, p.Arg401His, p.Arg401Leu and p.Arg401Ser) have also been reported to be causative for MH. In addition, this variant has been reported to be causative for recessive myopathy (Amburgey et al. 2013. PubMed ID: 23919265). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. In summary, we conclude that the c.1201C>T variant is pathogenic for dominant inheritance of MH susceptibility and also recessive inheritance of RYR1-related myopathy. -
Malignant hyperthermia of anesthesia Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Inborn genetic diseases Uncertain: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