rs118192163

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PS4PS3_ModerateBS2PM1PP1_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 2163 of the RYR1 protein, p.(Arg2163His). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 16 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 14 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, PMID:9497245, PMID:21455645, PMID:15731587, PMID:23558838). This variant has been identified in three individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). Additional functional studies in dyspedic myotubes were published for this variant, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:12732639, PMID:15347586). 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 seven families, PP1_Strong (PMID:30236257, PMID:9497245). A REVEL score >0.85 (0.933) 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024593/MONDO:0007783/012

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic; drug response reviewed by expert panel P:6O:9

Conservation

PhyloP100: 9.94

Publications

33 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 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.

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.6488G>A	p.Arg2163His	missense_variant	Exon 39 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.6488G>A	p.Arg2163His	missense_variant	Exon 39 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250392

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727164

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

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:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:6Other:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Nov 20, 2013

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

- -

Oct 04, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second variant on the opposite allele (in trans) in a patient with arthrogryposis multiplex congenita and respiratory impairment in published literature (Brackmann et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: increased sensitivity to calcium- and halothane-induced intracellular calcium release when compared to the wild type channel (Tong et al., 1997; Avila et al., 2001); 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: 9873004, 20301565, 11524458, 30236257, 10757649, 16917943, 16732084, 16835904, 27586648, 28687594, 9497245, 35428369, 12124989, 12668474, 29169929, 19648156, 9334205) -

Mar 25, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:1Other:1

Mar 01, 1998

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 29, 2022

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 2163 of the RYR1 protein, p.(Arg2163His). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 16 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 14 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, PMID:9497245, PMID:21455645, PMID:15731587, PMID:23558838). This variant has been identified in three individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). Additional functional studies in dyspedic myotubes were published for this variant, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:12732639, PMID:15347586). 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 seven families, PP1_Strong (PMID:30236257, PMID:9497245). A REVEL score >0.85 (0.933) 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. -

RYR1-related disorder

Pathogenic:1

May 25, 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 2163 of the RYR1 protein (p.Arg2163His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (MHS) with or without central core disease and/or severe congenital myopathy (PMID: 9497245, 12124989, 19648156, 29169929, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12974). 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, 9873004, 11524458, 27586648, 28687594). For these reasons, this variant has been classified as Pathogenic. -

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

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

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

9.9

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.95

Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);

MVP

0.98

MPC

0.89

ClinPred

1.0

GERP RS

4.6

Varity_R

0.83

gMVP

0.97

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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