rs34934920

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

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 Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024515/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.017 ( 48 hom., cov: 32)

Exomes 𝑓: 0.023 ( 502 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:21O:1

Conservation

PhyloP100: 0.765

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: Benign. The variant received -8 ACMG points.

BA1

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.5360C>T	p.Pro1787Leu	missense_variant	Exon 34 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.5360C>T	p.Pro1787Leu	missense_variant	Exon 34 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2572

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00461

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0484

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0195

AC:

4749

AN:

243108

AF XY:

0.0214

show subpopulations

Gnomad AFR exome

AF:

0.00337

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0252

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00671

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0235

AC:

34311

AN:

1461176

Hom.:

502

Cov.:

AF XY:

0.0242

AC XY:

17599

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.00415

AC:

139

AN:

33474

American (AMR)

AF:

0.0134

AC:

599

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0263

AC:

687

AN:

26114

East Asian (EAS)

AF:

0.000302

AC:

AN:

39692

South Asian (SAS)

AF:

0.0421

AC:

3634

AN:

86252

European-Finnish (FIN)

AF:

0.00646

AC:

342

AN:

52910

Middle Eastern (MID)

AF:

0.0368

AC:

212

AN:

5768

European-Non Finnish (NFE)

AF:

0.0246

AC:

27338

AN:

1111876

Other (OTH)

AF:

0.0223

AC:

1348

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2242

4485

6727

8970

11212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1060

2120

3180

4240

5300

<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

AF:

0.0169

AC:

2569

AN:

152348

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1235

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00459

AC:

191

AN:

41580

American (AMR)

AF:

0.0175

AC:

268

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0479

AC:

231

AN:

4826

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0240

AC:

1633

AN:

68028

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0230

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0232

AC:

199

ExAC

AF:

0.0191

AC:

2315

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0259

ClinVar

Significance: Benign

Submissions summary: Benign:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Mar 04, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 21, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: BS1, BS2 -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Benign:5

Mar 17, 2021

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance:Benign

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 Proline with Leucine at codon 1787 of the RYR1 protein, p.(Pro1787Leu). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0413, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. -

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1-related disorder

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Malignant hypothermia

Benign:1

Mar 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;D

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

N;N

PhyloP100

0.77

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.055

Sift

Benign

0.10

T;T

Polyphen

0.016

B;B

Vest4

0.32

MPC

0.66

ClinPred

0.020

GERP RS

-0.016

Varity_R

0.059

gMVP

0.53

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over