Variant rs193922816 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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.

PM5

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 linkuse as main transcript	c.7360C>T	p.Arg2454Cys	missense_variant	46/106	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.7360C>T	p.Arg2454Cys	missense_variant	46/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7360C>T	p.Arg2454Cys	missense_variant	46/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.814C>T	p.Arg272Cys	missense_variant, NMD_transcript_variant	7/49	1		ENSP00000470927
RYR1	ENST00000599547.6 linkuse as main transcript	c.7360C>T	p.Arg2454Cys	missense_variant, NMD_transcript_variant	46/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152184

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251200

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135876

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

9

AN:

1461466

Hom.:

0

Cov.:

31

AF XY:

0.00000550

AC XY:

4

AN XY:

727030

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152184

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74348

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000482

Hom.:

0

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:10Other:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2024	Reported in association with malignant hyperthermia (PMID: 10484775); Published functional studies demonstrate a damaging effect as this variant results in abnormal calcium release (PMID: 16958617); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27586648, 24433488, 31447099, 12668474, 33767344, 16958617, 10484775) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2020	- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 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 arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000065. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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_Moderate (PMID: 10484775, 10612851, 16163667). This variant segregates with MHS in 3 individuals, PP1 (PMI: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). 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). Another variant that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757). A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and cysteine. The variant is classified as a diagnostic malignant hyperthermia (MH) mutation by the European Malignant Hyperthermia Group (EMHG). It is present in a large population cohort at a frequency of 0.002% (rs193922816, 4/251,200 alleles, 0 homozygotes in gnomAD v2.1.1). The variant has been identified in multiple MH susceptible families and segregates with the condition (PMID: 10484775, 10612851, 12411788, 29608462). Further, it has been identified in association with a clinical reaction consistent with MH under anaesthesia and confirmed by a positive in vitro contracture test (PMID: 10484775), and demonstrates gain-of-function in well-established in vitro functional studies (PMID: 16163667, 27586648). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Additionally, a different amino acid substitution at this residue (p.Arg2454His) is also an EMHG diagnostic MH mutation. Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PM5, PP1_Moderate, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	This variant is a known pathogenic variant in the RYR1 gene. This variant has been reported in multiple individuals and at least one family with malignant hyperthermia in the medical literature (Brandt 1999, Gencik 2000, Monnier 2002). This variant falls within a region known to be important for normal sarcoplasmic reticulum function (Bannister 2007, Murayama 2016). It has been observed in four individuals reported in the gnomAD database (gnomad.broadinstitute.org). Based on this evidence we interpret this as a pathogenic variant. PS4-moderate; PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 09, 2023	This missense variant replaces arginine with cysteine at codon 2454 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 causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667, 27586648). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 6 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 10484775, 10612851, 12411788, 16163667, 24433488, 25611019, 25989378, 30864471) and has been shown to segregate with disease in a small German kindred (PMID: 10484775). This variant has been identified in 4/251200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg2454His, is known to cause disease (ClinVar variation ID: 65980), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2454 of the RYR1 protein (p.Arg2454Cys). This variant is present in population databases (rs193922816, gnomAD 0.006%). This missense change has been observed in individuals with malignant hyperthermia (MH) (PMID: 10484775, 10612851, 12411788, 16163667). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133202). 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: 16163667, 16958617, 27586648). This variant disrupts the p.Arg2454 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10051009, 10484775, 15448513, 16163667, 27586648). 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. -

Malignant hyperthermia of anesthesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 21, 2016

The p.Arg2454Cys variant in RYR1 has been reported in 4 individuals with maligna nt hyperthermia and segregated with disease in 2 affected relatives from 1 famil y (Brandt 1999, Gencik 2000, Monnier 2002, Monnier 2005). This variant has been identified in 2/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922816). In vitro functio nal studies provide some evidence that the p.Arg2454Cys variant may impact prote in function (Monnier 2005, Bannister 2007). However, these types of assays may n ot accurately represent biological function. Another variant at the same amino a cid position (p.Arg2454His) is likely disease causing for malignant hyperthermia , increasing the likelihood that the change to a cysteine would also be disease causing. Computational prediction tools and conservation analysis suggest that t he p.Arg2454Cys variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg2454Cys variant is likely 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

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

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.38

D

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.80

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.53

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.95

Loss of MoRF binding (P = 0.05);Loss of MoRF binding (P = 0.05);

MVP

1.0

MPC

0.41

ClinPred

0.98

D

GERP RS

4.0

Varity_R

0.60

gMVP

0.94

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.

rs193922816

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