Variant rs193922803 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.7063C>T	p.Arg2355Trp	missense_variant	44/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.7063C>T	p.Arg2355Trp	missense_variant	44/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.7063C>T	p.Arg2355Trp	missense_variant	44/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 link	n.514C>T		non_coding_transcript_exon_variant	5/49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 link	n.7063C>T		non_coding_transcript_exon_variant	44/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152104

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000209

AC:

5

AN:

239396

Hom.:

0

AF XY:

0.0000306

AC XY:

4

AN XY:

130734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

27

AN:

1447118

Hom.:

0

Cov.:

33

AF XY:

0.0000180

AC XY:

13

AN XY:

720356

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152104

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:11Other:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 13, 2024	This missense variant replaces arginine with tryptophan at codon 2355 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 patient myotubes and lymphoblastoid cells expressing this variant have shown increased sensitivity to caffeine, 4-CmC, and halothane compared to cell expressing wild-type RYR1 (PMID: 15210166, 24361844, 28403410). This variant has been reported in more than 10 families and individuals affected with malignant hyperthermia susceptibility (PMID: 15210166, 15210166, 19648156, 23558838, 24361844, 24361844, 25256590, 28403410, 28403410, 30236257). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 families (PMID: 15210166, 24361844, 28403410). This variant has been identified in 5/239396 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	Color Diagnostics, LLC DBA Color Health	Mar 29, 2023	This missense variant replaces arginine with tryptophan at codon 2355 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 patient-derived myotubes and lymphoblastoid cells have shown this variant increases sensitivity to caffeine, 4-CmC, and halothane compared to cell expressing wild-type RYR1 (PMID: 15210166, 24361844, 28403410). This variant has been reported in more than 10 families and individuals affected with malignant hyperthermia susceptibility (PMID: 15210166, 15210166, 19648156, 23558838, 24361844, 24361844, 25256590, 28403410, 28403410, 30236257). It has been shown that this variant segregates with malignant hyperthermia susceptibility in 8 families (PMID: 15210166, 24361844, 28403410). This variant has been identified in 5/239396 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 panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 19, 2021	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 tryptophan at codon 2355 of the RYR1 protein, p.(Arg2355Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000036, a frequency consistent with pathogenicity for MHS. This variant has been reported in 18 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 17 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, 23558838, 24361844, 12123492, 15210166, 23460944, 25256590, 22473935). This variant segregates with MHS in at least 12 individuals, PP1_Strong (PMID: 30236257, 24361844). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 28403410). Additionally, two ex vivo studies using myotubes and B-lymphocytes, showed increased sensitivity to RYR1 agonists in multiple unrelated individuals (PMID: 15210166, 24361844). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.861) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Aug 30, 2024	ACMG Criteria: PM2_p, PS3, PS4, PP3, PP5, PP1; Variant was found in heterozygous state -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2021	Published functional studies demonstrate a damaging effect, as mutant protein results in altered receptor function as compared to wild-type (Wehner et al., 2004; Schiemann et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 30611313, 23558838, 22473935, 12123492, 24361844, 15210166, 16917943, 30236257, 30842289, 28403410, 31301762, 32381029, 30499100, 32528171, 33087929) -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 15, 2017

- -

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2023

This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 15210166, 19648156, 23558838, 24361844). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (PMID: 15210166, 24361844, 28403410). 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. ClinVar contains an entry for this variant (Variation ID: 133183). This variant is present in population databases (rs193922803, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2355 of the RYR1 protein (p.Arg2355Trp). -

Malignant hyperthermia of anesthesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2022

The p.Arg2355Trp variant in RYR1 has been previously reported in at least 14 probands with malignant hyperthermia susceptibility and segregated in >10 affected family members (Broman 2015, Miller 2018, Brandom 2013, Schiemann 2014, Carpenter 2009, Klein 2012, Robinson 2006, McWilliams 2002, Jokela 2019, Merritt 2014, Wehner 2004). The variant has also been reported in 2 individuals with myopathy, who were compound heterozygous for a second variant (Garibaldi 2019, Klein 2012). In vitro functional studies also support that this variant results in malignant hyperthermia reaction, as increased calcium released was observed in response to caffeine, 4-chloro-m-cresol, and/or halothane in cells (Schiemann 2014, Merritt 2017, Wehner 2004). This variant has been identified in 1/10010 of Ashkenazi Jewish chromosomes and in 4/111684 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 133183). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP criteria applied: PS4_Moderate, PP1_Strong, PM2, PS3_Moderate, PP3, PM3_Supporting. -

Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Central core myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 18, 2024

- -

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

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

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

desflurane 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

succinylcholine 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

sevoflurane 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

isoflurane 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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.42

D

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.87

D

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.62

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.97

D

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.84

D

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.86

MutPred

0.95

Gain of ubiquitination at K2360 (P = 0.0329);Gain of ubiquitination at K2360 (P = 0.0329);

MVP

0.93

MPC

0.75

ClinPred

0.98

D

GERP RS

4.0

Varity_R

0.85

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.

rs193922803

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