rs121918593

Positions:

chr19-38499993-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PM1PS4PS3PP1_StrongPP3_ModerateBS2

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 glycine with arginine at codon 2434 of the RYR1 protein, p.(Gly2434Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000078, a frequency consistent with pathogenicity for MHS. This variant has been reported in 178 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 174 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, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant has been identified in six individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID:27586648). p.(Gly2434Arg) knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes, PS3 (PMID:30236258). 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 20 individuals, PP1_Strong (PMID:7849712, 11575529, 12059893, 25960145). A REVEL score >0.85 (0.956) 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, PS4, PM1, PP1_Strong, PP3_Moderate, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024747/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:23O:9

Conservation

PhyloP100: 9.98

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]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7300G>A	p.Gly2434Arg	missense_variant	45/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7300G>A	p.Gly2434Arg	missense_variant	45/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7300G>A	p.Gly2434Arg	missense_variant	45/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.754G>A	p.Gly252Arg	missense_variant, NMD_transcript_variant	6/49	1		ENSP00000470927
RYR1	ENST00000599547.6 linkuse as main transcript	c.7300G>A	p.Gly2434Arg	missense_variant, NMD_transcript_variant	45/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251254

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727218

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:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:23Other:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:10Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 24, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is also referred to as p.Gly2433Arg and p.Gly2435Arg in some published literature. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant segregates with disease in multiple families with susceptibility to malignant hyperthermia. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired calcium homeostasis (PMID: 9334205, 30236258, 27586648). Computational tools predict that this variant is damaging. -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RYR1: PP1:Strong, PS3, PS4, PM1, PP3, BS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 25, 2020	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2016	The G2434R variant in the RYR1 gene has been published previously as a pathogenic variant associated with malignant hyperthermia (Keating et al., 1994; Carpenter et al., 2009; Riazi et al., 2014). The G2434R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G2434R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Based on the ACMG recommendations, G2434R is interpreted as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 08, 2018	- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 28, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Jul 11, 2022	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 glycine with arginine at codon 2434 of the RYR1 protein, p.(Gly2434Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000078, a frequency consistent with pathogenicity for MHS. This variant has been reported in 178 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 174 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, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant has been identified in six individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). p.(Gly2434Arg) knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes, PS3 (PMID:30236258). 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 20 individuals, PP1_Strong (PMID: 7849712, 11575529, 12059893, 25960145). A REVEL score >0.85 (0.956) 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, PS4, PM1, PP1_Strong, PP3_Moderate, BS2. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	This missense variant replaces glycine with arginine at codon 2434 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). A study using genetically engineered mice has shown that mice carrying this variant develop malignant hyperthermia when exposed to halothane (PMID: 30236258). Further, functional studies on myotubes from the genetically engineered mice showed increased sensitivity to caffeine, halothane, and KCI in comparison to myotubes expressing wild-type RYR1 (PMID: 30236258). This variant has been reported in over 100 families and individuals affected with malignant hyperthermia susceptibility (PMID: 21455645, 23558838, 23842196, 24433488, 25268394, 25735680, 25960145, 27646467, 30236257, 30788618, 31206373). This variant has been identified in 11/282648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	This c.7300G>A (p.Gly2434Arg) variant in the RYR1 gene has previously been reported in multiple patients with malignant hyperthermia [PMID 7849712, 23842196, 19648156, 11668625]. This variant has been functionally characterized and shown to have an increased sensitivity to activating concentrations of Ca2+ and to caffeine and 4-chloro-m-cresol in vitro. The variant is classified as pathogenic by the European malignant hyperthermia group (https://emhg.org). This variant has been observed in one 3 heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-38990633-G-A). Glycine at position 2434 of the RYR1 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Gly2434Arg change to be deleterious. It is thus interpreted as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.7300G>A (p.Gly2434Arg) variant, located on the exon 45 of the RYR1 gene, replaces glycine with arginine at codon 2434 of the RYR1 protein (p.Gly2434Arg). This missense change has been observed in >100 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant segregates with malignant hyperthermia (MHS) in at least 20 individuals (PMID: 7849712, 11575529, 12059893, 25960145). 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: 27586648). Such effect was confirmed in human skeletal muscle specimens isolated from MHS individuals carrying this RYR1 variant (PMID:9030597). Additionally, p.Gly2434Arg knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics, and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes (PMID:30236258). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. For these reasons, the c.7300G>A (p.Gly2434Arg) variant of RYR1 is classified as pathogenic. -
risk factor, no assertion criteria provided	literature only	OMIM	Feb 21, 1997	- -

Malignant hyperthermia of anesthesia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	This sequence change in RYR1 is predicted to replace glycine with arginine at codon 2434, p.(Gly2434Arg). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in exon 45 in the central region, amino acids 2,101-2,458, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (149/1,180,014 alleles) in the European (non-Finnish) population. The variant is the most common malignant hyperthermia susceptibility (MHS) variant detected in the United Kingdom (PMID: 30236257), and segregates with MHS in multiple families (PMID: 7849712). In vitro functional studies are supportive of a gain of function effect on intracellular calcium release and a knock-in mouse model recapitulates the human MHS response (PMID: 9334205, 27586648, 30236258). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.965). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PP1_Strong, PP3_Moderate, PS3, PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 15, 2020	The p.Gly2434Arg variant in RYR1 is an established pathogenic variant for malignant hyperthermia (MH). It has been reported in >100 individuals with MH and segregated with disease in >100 affected relatives from several families (Keating 1994, Phillips 1994, Richter 1997, Sambuughin 2001, Carpenter 2009, Dlamini 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 12970) and has been identified in 0.008% (10/129020) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of MH in the general population. In-vitro functional studies provide evidence that the p.Gly2434Arg variant may impact protein function (Richter 1997, Tong 1999, Girard 2001, Weigl 2004). In summary, this variant meets criteria to be classified as pathogenic for MH in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -

Central core myopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 04, 2023	The RYR1 c.7300G>A variant is classified as Pathogenic (PS3, PS4, PP3, PP5) The RYR1 c.7300G>A variant is a single nucleotide change in exon 45/106 of the RYR1 gene, which is predicted to change the amino acid glycine at position 2434 in the protein to arginine. The variant has been frequently reported in the literature in association with a malignant hyperthermia and central core disease (PS4). This variant is present at low frequency in population databases. Lopez et al (2018) reports that RYR1 p.G2435R knock-in mice demonstrated gene dose-dependent in vitro and in vivo responses to pharmacological and environmental stressors that parallel those seen in patients with the human RYR1 variant p.G2434R (PMID: 30236258) (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs121918593) and in the HGMD database: CM941269. It has been reported as Drug response by other diagnostic laboratories (ClinVar Variation ID: 12970), including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (PP5). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 30, 2022	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

The c.7300G>A (p.G2434R) alteration is located in exon 45 (coding exon 45) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 7300, causing the glycine (G) at amino acid position 2434 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (11/282,648) total alleles studied. The highest observed frequency was 0.008% (10/129,020) of European (non-Finnish) alleles. This alteration has been reported heterozygous in multiple patients and their family members with features consistent with malignant hyperthermia (Keating, 1994; Riazi, 2014; Snoeck, 2015; Witting, 2018; Knuiman, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration has been shown in vitro to enhance the sensitivity of RYR1 to activating concentrations of Ca2+ and to the exogenous ligands, caffeine and 4-chloro-m-cresol. The study also showed reduced sensitivity to inhibiting concentrations of Ca2+ and calmodulin, transferring the mutant Ca2+ release channel into a hyperexcitable state (Richter, 1997). Another study by Chen et al. (2017) showed that the p.G2434R alteration, when expressed in HEK293 cells, reduced the threshold for store overload-induced Ca2+ release (SOICR), allowing for spontaneous Ca2+ release from the sarcoplasmic reticulum, which has been proposed as the cause of uncontrolled muscle contraction. 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2434 of the RYR1 protein (p.Gly2434Arg). This variant is present in population databases (rs121918593, gnomAD 0.008%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 7849712, 9030597, 10484775, 11668625, 19648156, 23842196, 24433488). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly2433Arg. ClinVar contains an entry for this variant (Variation ID: 12970). 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: 9030597, 9334205). For these reasons, this variant has been classified as Pathogenic. -

methoxyflurane response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

halothane response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

desflurane response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

succinylcholine response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

sevoflurane response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

isoflurane response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.92

Gain of catalytic residue at G2434 (P = 0.0522);Gain of catalytic residue at G2434 (P = 0.0522);

MVP

0.99

MPC

0.40

ClinPred

0.74

GERP RS

4.0

Varity_R

0.90

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over