rs35364374

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 Glycine with Cysteine at codon 2060 of the RYR1 protein, p.(Gly2060Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.1562, 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/CA024556/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.051 ( 301 hom., cov: 32)

Exomes 𝑓: 0.068 ( 4145 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:18O:1

Conservation

PhyloP100: 0.786

Publications

43 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.6178G>T	p.Gly2060Cys	missense_variant	Exon 38 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.6178G>T	p.Gly2060Cys	missense_variant	Exon 38 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7770

AN:

152108

Hom.:

304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0718

Gnomad OTH

AF:

0.0654

GnomAD2 exomes

AF:

0.0685

AC:

17228

AN:

251328

AF XY:

0.0736

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.0746

Gnomad ASJ exome

AF:

0.0820

Gnomad EAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.0206

Gnomad NFE exome

AF:

0.0698

Gnomad OTH exome

AF:

0.0711

GnomAD4 exome

AF:

0.0684

AC:

99923

AN:

1461806

Hom.:

4145

Cov.:

AF XY:

0.0714

AC XY:

51946

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0124

AC:

415

AN:

33480

American (AMR)

AF:

0.0719

AC:

3217

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0869

AC:

2270

AN:

26134

East Asian (EAS)

AF:

0.00647

AC:

257

AN:

39698

South Asian (SAS)

AF:

0.153

AC:

13198

AN:

86256

European-Finnish (FIN)

AF:

0.0205

AC:

1093

AN:

53392

Middle Eastern (MID)

AF:

0.112

AC:

644

AN:

5766

European-Non Finnish (NFE)

AF:

0.0672

AC:

74768

AN:

1111964

Other (OTH)

AF:

0.0672

AC:

4061

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

5297

10594

15892

21189

26486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2752

5504

8256

11008

13760

<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:

0.0510

AC:

7768

AN:

152226

Hom.:

301

Cov.:

AF XY:

0.0500

AC XY:

3720

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0124

AC:

517

AN:

41550

American (AMR)

AF:

0.0566

AC:

865

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3468

East Asian (EAS)

AF:

0.00444

AC:

AN:

5180

South Asian (SAS)

AF:

0.160

AC:

770

AN:

4824

European-Finnish (FIN)

AF:

0.0174

AC:

185

AN:

10610

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0718

AC:

4880

AN:

67992

Other (OTH)

AF:

0.0666

AC:

141

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

359

718

1076

1435

1794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0640

Hom.:

1000

Bravo

AF:

0.0491

TwinsUK

AF:

0.0642

AC:

238

ALSPAC

AF:

0.0791

AC:

305

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0713

AC:

613

ExAC

AF:

0.0692

AC:

8407

Asia WGS

AF:

0.0910

AC:

314

AN:

3478

EpiCase

AF:

0.0778

EpiControl

AF:

0.0772

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:7

Jul 31, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2018

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly2060Cys in exon 38 of RYR1: This variant is not expected to have clinical s ignificance because it has been identified in 7.1% (613/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs35364374). -

Malignant hyperthermia, susceptibility to, 1

Benign:5

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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 Glycine with Cysteine at codon 2060 of the RYR1 protein, p.(Gly2060Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.1562, 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. -

Jan 12, 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. -

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2010

GeneReviews

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

not provided

Benign:1Other: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

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1-related disorder

Benign:1

Feb 04, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;D

Eigen

Benign

0.16

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PhyloP100

0.79

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.17

Sift

Benign

0.058

T;T

Polyphen

0.97

D;P

Vest4

0.51

MPC

0.46

ClinPred

0.014

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.14

Mutation Taster

=97/3

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