rs118192122

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS4BS2_SupportingPS3_ModeratePM1PP1_StrongPP3_Moderate

This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of arginine with histidine at codon 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 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 (PMID:30236257, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID:30236257).Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID:19191333). 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 11 individuals/families PP1_Strong (PMID:12059893, 10051009). A REVEL score >0.85 (0.923) 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_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024781/MONDO:0007783/012

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:15O:8

Conservation

PhyloP100: 9.99

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

malignant hyperthermia, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
King-Denborough syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant hyperthermia of anesthesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
benign Samaritan congenital myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myopathy with myasthenic-like onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.7361G>A	p.Arg2454His	missense_variant	Exon 46 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.7361G>A	p.Arg2454His	missense_variant	Exon 46 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251210

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461498

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5556

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000100

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:15Other:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Pathogenic:7

Jun 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 2454 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). 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 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Mar 19, 2021

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 histidine at codon 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 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 (PMID: 30236257, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). 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 11 individuals/families PP1_Strong (PMID: 12059893, 10051009). A REVEL score >0.85 (0.923) 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_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate. -

Jul 28, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.7361G>A (p.Arg2454His) variant in exon 46 of the RYR1 gene has been reported in multiple individuals with susceptibility to malignant hyperthermia that was diagnosed either by a well-defined laboratory diagnostic test or patients developed malignant hyperthermia crisis during anesthesia (PMID: 16163667, 19648156, 10051009, 20301565). Independently performed functional assays also support the pathogenicity of this variant (PMID, 19191333, 16163667, 27586648). Moreover, European Malignant Hyperthermia Group (EMHG) has categorized this variant as diagnostic for susceptibility to malignant hyperthermia https://emhg.org/genetics/mutations-in-ryr1/. The c.7361G>A (p.Arg2454His) variant in the RYR1 gene is classified as pathogenic . -

May 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7361G>A (p.Arg2454His) variant, located on the exon 46 of the RYR1 gene, replaces arginine with histidine at codon 2454 of the RYR1 protein (p.Arg2454His). This missense change has been observed in multiple 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, 12059893, 16163667, 19648156, 24433488, 11575529, 10051009, 10823104, 17081152, 21455645, 23558838, 25960145). This variant segregates with malignant hyperthermia (MHS) in several families (PMID: 30236257, 12059893, 10051009). This missense variant is located in a mutational hot spot region that contributes to MHS (PMID: 21118704). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). An ex vivo assay in patient-derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). This variant is rare in the general population according to gnomAD (2/251210 chromosomes). The variant is reported as pathogenic in ClinVar (ID: 65980) and reviewed by the expert panel. Another alteration affecting the same amino acid, c.7360C>T (p.Arg2454Cys) has been classified as pathogenic by the expert panel in ClinVar (ID: 133202). Therefore, the c.7361G>A (p.Arg2454His) variant in the RYR1 gene is classified as pathogenic. -

Jul 21, 2023

deCODE genetics, Amgen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

The variant NM_000540.3:c.7361G>A (chr19:38500643) in RYR1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic and is one of the diagnostic MH variants (https://www.emhg.org/diagnostic-mutations). Based on ACMG criteria (PS3, PM2, PP3, PP4, PP5_Strong) this variant classifies as pathogenic. -

not provided

Pathogenic:4Other:1

Mar 11, 2016

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously, in the heterozygous state, as a pathogenic variant associated with malignant hyperthermia (PMID: 10051009, 12059893, 19648156); B-lymphocytes from individuals with the R2454H variant displayed an increased extracellular acidification rate compared with wild-type cells, suggesting that the R2454H variant causes increased calcium channel activity (PMID: 19191333); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28325813, 26951757, 19648156, 31206373, 34462577, 19191333, 27586648, 28682948, 28687594, 12059893, 30236257, 30499100, 30788618, 32174957, 31447099, 17081152, 37937776, 10051009, 12668474, 33767344) -

RYR1-related disorder

Pathogenic:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2454 of the RYR1 protein (p.Arg2454His). This variant is present in population databases (rs118192122, gnomAD 0.007%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (MHS) (PMID: 10051009, 12059893, 19191333, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65980). 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: 19191333, 19648156). 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: 10612851, 12411788, 16163667). 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

Jun 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.7361G>A (p.Arg2454His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251210 control chromosomes. c.7361G>A has been reported in the literature in the heterozygous state in multiple individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility (example, Barone_1999, Carpenter_2009, Miller_2018), and segregated with disease among several related individuals. These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have shown this variant causes enhanced ryanodine binding and decreased the Ca2+ threshold required for spontaneous muscle contraction (example, Chen_2017, Murayama_2016). The following publications have been ascertained in the context of this evaluation (PMID: 10051009, 19648156, 28687594, 30236257, 27586648). ClinVar contains an entry for this variant (Variation ID: 65980). Based on the evidence outlined above, the variant was classified as pathogenic. -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Pathogenic:1

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Pathogenic:1

May 11, 2010

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

methoxyflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

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

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

halothane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

desflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

succinylcholine response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

sevoflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

isoflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.93

Loss of MoRF binding (P = 0.0603);Loss of MoRF binding (P = 0.0603);

MVP

1.0

MPC

0.46

ClinPred

0.99

GERP RS

4.0

Varity_R

0.62

gMVP

0.93

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over