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19-38457545-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000540.3(RYR1):c.1840C>T(p.Arg614Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,drug response (β˜…β˜…β˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R614L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

9
7
1

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:24O:9

Conservation

PhyloP100: 2.77
Variant links:
Genes affected
RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000540.3
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr19-38457546-G-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 133108.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, RYR1
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.917
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-38457545-C-T is Pathogenic according to our data. Variant chr19-38457545-C-T is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 12964.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38457545-C-T is described in Lovd as [Pathogenic]. Variant chr19-38457545-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR1NM_000540.3 linkuse as main transcriptc.1840C>T p.Arg614Cys missense_variant 17/106 ENST00000359596.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.1840C>T p.Arg614Cys missense_variant 17/1065 NM_000540.3 A2P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.1840C>T p.Arg614Cys missense_variant 17/1051 P4P21817-2
RYR1ENST00000599547.6 linkuse as main transcriptc.1840C>T p.Arg614Cys missense_variant, NMD_transcript_variant 17/802

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000112
AC:
17
AN:
152068
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000875
AC:
22
AN:
251496
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000691
AC:
101
AN:
1461868
Hom.:
0
Cov.:
33
AF XY:
0.0000619
AC XY:
45
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.0000800
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000112
AC:
17
AN:
152186
Hom.:
0
Cov.:
30
AF XY:
0.0000672
AC XY:
5
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000164
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000824
AC:
10
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic; drug response
Submissions summary: Pathogenic:24Other:9
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:11Other:1
Pathogenic, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJan 08, 2024This missense variant replaces arginine with cysteine at codon 614 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 in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 1996- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This sequence change in RYR1 is predicted to replace arginine with cysteine at codon 614, p.(Arg614Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 17 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (25/129,186 alleles) in the European (non-Finnish) population. The prevalence of the variant in individuals with malignant hyperthermia susceptibility (MHS) is significantly increased compared with the prevalence in controls (Odds Ratio 51.1, 95% CI: 26.4-98.7) (PMID: 30236257; gnomAD v2.1 European non-Finnish). It has also been identified in cases with dominant and recessive central core disease, severe statin myopathy, and recurrent rhabdomyolysis (PMID: 14985404, 21795085, 29635721, 33458582). The variant has been reported to segregate with MHS in multiple families (PMID: 8602662, 11493496, 12411788). The variant demonstrates a gain of function effect on intracellular calcium release in a HEK293 assay indicating that this variant impacts protein function (PMID: 9334205). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Another missense variant c.1841G>T, p.(Arg614Leu) in the same codon has been classified as pathogenic for MHS (ClinVar Variation ID: 133108). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Moderate, PM1, PM5, PP3. -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyJul 29, 2021ACMG codes:PS4M, PM2, PM5, PP3, PP5 -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 16, 2017This c.1840C>T (p.Arg614Cys) variant in the RYR1 gene has been reported in multiple unrelated individuals with malignant hyperthermia (PMID: 1774074, 7762556, 10051009, 10484775, 19648156, 23842196, 11668625) or myopathy (PMID: 21795085). This variant has been shown to segregate with features of malignant hyperthermia in multiple families (PMID: 7762556, 7586638, 9520251). The c.796G>A variant is rare in the general population and arginine at position 614 of the RYR1 protein is highly evolutionarily conserved. The c.1840C>T (p.Arg614Cys) variant in the RYR1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 17, 2023This missense variant replaces arginine with cysteine at codon 614 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 in HEK293 cells and myotubes have shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 9334205, 12732639, 26115329). This variant has been reported in more than 20 individuals and families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145, 23842196, 24433488, 25268394, 25735680, 30236257). It has been shown that this variant segregates with disease in multiple families affected with malignant hyperthermia susceptibility (PMID: 10352931, 11493496, 12411788, 25960145). A different variant affecting the same codon, c.1841G>T (p.Arg614Leu), is considered to be disease-causing (ClinVar variation ID: 133108), suggesting that Arg at this position is important for the protein function. This variant has been described as a common variant associated with malignant hyperthermia in the Western European population (PMID: 11668625, 21455645). This variant has been identified in 30/282862 chromosomes 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 panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenMar 17, 2021This 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 614 of the RYR1 protein, p.(Arg614Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00019, a frequency consistent with pathogenicity for MHS. This variant has been reported in over 100 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 100 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:24433488, PMID:16163667, PMID:30236257, and others). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:10484775). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS (PMID: 21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg614Leu), PM5 (PMID:16917943). p.(Arg614Cys) segregates with MHS in 38 individuals PP1_Strong, (PMID:25960145, PMID:7586638, PMID:11493496 and others). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. Criteria implemented: PS3_Moderate, PS4, PM5, PP1_Strong, PP3_Moderate, BS2_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). -
Pathogenic, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MΓΌnchenJan 11, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 18, 2024Criteria applied: PS4,PP1_STR,PS3_MOD,PM5,PP3,BS2_MOD -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJan 25, 2022- -
not provided Pathogenic:7Other:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 15, 2021One of the most commonly identified RYR1 variants among individuals of Western European backgrounds (Rueffert et al., 2002; Kraeva et al., 2011); Published functional studies demonstrate a damaging effect, as the variant is sufficient to induce malignant hyperthermic episodes by causing impaired calcium and magnesium inhibition and reduced activation of the mutant protein at calcium concentrations typical of normal myotubes at rest (Tong et al., 1997; Yang et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 21455645, 25637381, 7511586, 30325262, 12124989, 31206373, 24195946, 9334205, 21795085, 12732639, 11668625, 9873004, 23842196, 12059893, 1774074, 19648156, 8602662, 12411788, 29635721, 29382405, 30788618, 30499100, 30236257, 29730239, 30208288, 30611313, 31016048, 31447099, 33278783, 33259453, 31589614, 10352931, 33587123, 14500992, 11493496, 11553045, 32665702, 10756965, 25214167, 32528171) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 29, 2023- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024RYR1: PP1:Strong, PS3, PS4, PM5, PP3 -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJan 07, 2022- -
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
RYR1-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 24, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 614 of the RYR1 protein (p.Arg614Cys). This variant is present in population databases (rs118192172, gnomAD 0.02%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 1774074, 8602662, 10352931, 11493496, 11668625, 12411788, 19648156, 21455645, 21795085, 23842196). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12964). 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: 9334205, 11668625, 12732639). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 11, 2023The RYR1 c.1840C>T variant is predicted to result in the amino acid substitution p.Arg614Cys. This variant has been conclusively established to be causative for malignant hyperthermia (MH) (www.emhg.org; Gillard et al. 1991. PubMed ID: 1774074; Otsu et al. 1994. PubMed ID: 7511586; Quane et al. 1997. PubMed ID: 9389851; Tong et al. 1997. PubMed ID: 9334205; Robinson et al. 2006. PubMed ID: 16917943). Functional studies in HEK293 cells indicate this variant results in increased caffeine sensitivity and abnormal ryanodine receptor function (Referred to R615C in Murayama et al. 2015. PubMed ID: 26115329). A different substitution at the same amino acid has also been reported to be causative (p.Arg614Leu). An expert ClinGen MH panel has classified this variant as pathogenic for MH (www.ncbi.nlm.nih.gov/clinvar/variation/12964). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38948185-C-T). This variant is interpreted as pathogenic. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org). -
Malignant hyperthermia of anesthesia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingNational Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of HealthAug 06, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 07, 2019The p.Arg614Cys variant in RYR1 has been reported in >30 individuals with malignant hyperthermia, and segregated with disease in more than 6 affected relatives from more than 3 families (Gillard 1991, Hogan 1992, Serfas 1996, Fortunato 1999, Rueffert 2001, Girard 2001, Muniz 2003, Vladutiu 2011, Klingler 2014, LMM unpublished data). In vitro functional studies provide some evidence that the p.Arg614Cys variant may impact protein function (Tong 1999, 2003, Girard 2001). Animal models in pigs further support a contribution to malignant hyperthermia (Ostu 1991). This variant has been identified in 0.02% (24/126704) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for malignant hyperthermia in an autosomal dominant manner. ACMG/AMP Criteria applied: PS3, PS4, PP1_Moderate. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 31, 2024The c.1840C>T (p.R614C) alteration is located in coding exon 17 of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 1840, causing the arginine (R) at amino acid position 614 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.011% (30/282862) total alleles studied. The highest observed frequency was 0.019% (25/129186) of European (non-Finnish) alleles. Multiple individuals with this alteration have been reported with MH (Rueffert, 2001A; Rueffert, 2001B; Carpenter, 2009; Gonsalves, 2013). Two siblings were described with this variant in trans with p.G215E with severe presentation of CCD with muliple arthryogyposis, severe hypotonia and amyotrophy, respiratory mechanical assistance, and multiple malformations including short femurs, facial dysmorphims, and bilateral clinodactyly of the second and fifth fingers (Romero, 2003). At 9 years of age the older child had delayed motor development, ptosis, strabismus, scoliosis and amyotrophy (Romero, 2003). The younger brother died at 32 weeks gestation with severe CCD congenital myopathy as well (Romero, 2003). Another alteration at the same codon, c.1841G>T (p.R614L), has been detected in individuals with a positive IVCT test and MH diagnosis (Barone, 1999). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 13, 2021- -
methoxyflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.46
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.4
D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.75
MVP
0.95
MPC
1.2
ClinPred
0.95
D
GERP RS
3.8
Varity_R
0.62
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118192172; hg19: chr19-38948185; COSMIC: COSV100616513; API