rs137933390

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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, 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/CA024433/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 19 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:5B:19

Conservation

PhyloP100: 4.86

Publications

29 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.4178A>G	p.Lys1393Arg	missense_variant	Exon 29 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.4178A>G	p.Lys1393Arg	missense_variant	Exon 29 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00273

AC:

617

AN:

225862

AF XY:

0.00269

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00225

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00194

GnomAD4 exome

AF:

0.00353

AC:

5110

AN:

1447116

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

2472

AN XY:

718420

show subpopulations

African (AFR)

AF:

0.000904

AC:

AN:

33174

American (AMR)

AF:

0.00209

AC:

AN:

42050

Ashkenazi Jewish (ASJ)

AF:

0.000116

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39134

South Asian (SAS)

AF:

0.00

AC:

AN:

84188

European-Finnish (FIN)

AF:

0.00210

AC:

110

AN:

52478

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00428

AC:

4729

AN:

1104696

Other (OTH)

AF:

0.00245

AC:

147

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

302

603

905

1206

1508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00277

AC:

421

AN:

152250

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41548

American (AMR)

AF:

0.00170

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00476

AC:

324

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00387

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00582

AC:

ExAC

AF:

0.00245

AC:

297

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:5Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:6

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in individuals with features of RYR1-related disorders, but familial segregation information was not always included and some individuals were noted to have other potentially causative variants (Vukcevic et al., 2010; Dlamini et al., 2013; Loseth et al., 2013; Gillies et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 20142353, 27153395, 25637381, 25985138, 23329375, 24195946, 25735680, 23628358, 28496993, 30788618, 30916033) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 03, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RYR1 c.4178A>G, p.Lys1393Arg variant (rs137933390) has been identified in several individuals with clinical suspicion for malignant hyperthermia susceptibility (MHS) syndrome or other related myopathy (Bick 2017, Gillies 2015, Loseth 2013, Vukcevic 2010). Additionally, a cell line isolated from an MHS patient showed increased sensitivity to 4-chloro-m-cresol (Vukcevic 2010). However, variant has been identified at high allele frequency in several control populations, and is found in the non-Finnish European population with an allele frequency of 0.46% (537/ 115776 alleles, including 2 homozygotes) in the Genome Aggregation Database. Due to this high population frequency, the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel considers this variant benign with respect to autosomal dominant MHS (ClinVar Variation ID: 93269). However, this population frequency alone is not high enough alone to rule out a potential role with respect to the recessive myopathies associated with loss of function variation in RYR1. Therefore, while considered benign for MHS specifically, the overall classification of this variant is uncertain. References: Bick D et al. Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. J Pediatr Genet. 2017 Jun;6(2):61-76. PMID: 28496993 Gillies RL et al. Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesth Intensive Care. 2015 Mar;43(2):157-66. PMID: 25735680. Loseth S et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013 Jun;260(6):1504-10. PMID: 23329375. Vukcevic M et al. Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. Anesth Analg. 2010 Jul;111(1):185-90. PMID: 20142353. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: BS2 -

Dec 01, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1

Benign:5

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is predicted to replace lysine with arginine at codon 1393 of the RYR1 protein (p.(Lys1393Arg)). The lysine residue is conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between lysine and arginine. It is not in an annotated domain. The variant is present in a large population cohort at a frequency of 0.46% in the European non-Finnish population (rs137933390, gnomAD v2.1.1 and v3.0). In comparison, the variant was present at a frequency of 0.46% in a cohort of individuals with malignant hyperthermia susceptibility (PMID: 24195946). This variant has been seen in at least 13 individuals with malignant hyperthermia susceptibility, including some individuals where another RYR1 variant was identified (PMID: 24195946, 19346234, 25960145, 23558838, 24433488, 25735680, 28326467), as well as being present in individuals with myopathy, rhabdomyolysis and exertional heat stroke (PMID: 22473935, 23628358, 23329375, 26565425, 28496993), although several authors acknowledge the high population frequency and comment that the variant is unlikely to be pathogenic. This variant has been shown not to segregate with the malignant hyperthermia susceptibility phenotype in two unrelated families, although the pedigrees have not been confirmed (PMID: 25658027). It has been reported in at least three further individuals without malignant hyperthermia (PMID: 25614869). Functional data from a lymphoblastoid cell line demonstrated 4-chloro-m-cresol induced calcium release at a lower concentration, however it is unclear whether this is a true reflection of the skeletal myocyte (PMID: 20142353). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign/neutral effect, 1/6 algorithms predict deleterious effect, 1/6 algorithms have an unknown prediction). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as LIKELY BENIGN. The following criteria are met: BS1, BP5. -

May 28, 2019

Mendelics

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

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Jul 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 21, 2017

Athena Diagnostics

Significance:Uncertain significance

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

- -

RYR1-related disorder

Benign:2

Jul 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia of anesthesia

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 03, 2022

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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, 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. -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Feb 09, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Feb 09, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.056

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.2

L;L

PhyloP100

4.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.30

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.34

T;T

Polyphen

0.39

B;B

Vest4

0.56

MVP

0.98

MPC

0.37

ClinPred

0.017

GERP RS

4.6

Varity_R

0.072

gMVP

0.54

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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