chr19-38543551-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. BS1PP3_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 tyrosine with cysteine at codon 3933 of the RYR1 protein, p.(Tyr3933Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.001332, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in six 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) (PMID:25958340, 20681998, 23558838, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.983) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is classified as Likely Benign, (PMID:29300386). Criteria implemented: PP3_Moderate, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023938/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21B:2O:1

Conservation

PhyloP100: 9.14

Publications

25 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: Likely_benign. The variant received -2 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.11798A>G	p.Tyr3933Cys	missense	Exon 86 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.11783A>G	p.Tyr3928Cys	missense	Exon 85 of 105	NP_001036188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR1	ENST00000359596.8	TSL:5 MANE Select	c.11798A>G	p.Tyr3933Cys	missense	Exon 86 of 106	ENSP00000352608.2
RYR1	ENST00000355481.8	TSL:1	c.11783A>G	p.Tyr3928Cys	missense	Exon 85 of 105	ENSP00000347667.3
RYR1	ENST00000594335.6	TSL:1	n.*2508A>G		non_coding_transcript_exon	Exon 83 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000867

AC:

218

AN:

251418

AF XY:

0.000949

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00118

AC:

1723

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

886

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.000984

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000533

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00140

AC:

1553

AN:

1112002

Other (OTH)

AF:

0.000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00109

AC:

166

AN:

152212

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41532

American (AMR)

AF:

0.00255

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68004

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

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:

0.00132

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000923

AC:

112

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:21Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7Other:1

Oct 16, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Y3933C and R3366H reported in cis, and in conjunction with an additional RYR1 variant on the opposite allele, have been reported in patients with core myopathies as well as malignant hyperthermia susceptibility in some cases (PMID: 25960145, 23919265, 25958340); Patients with only Y3933C and R3366H variants were reported to have malignant hyperthermia susceptibility or to be unaffected (PMID: 25958340, 25960145); 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: 36628841, 30788618, 30611313, 31321302, 32125936, 25637381, 20681998, 24055113, 25747005, 24950660, 23558838, 23919265, 25735680, 22473935, 21674524, 28269792, 28259615, 26332594, 25214167, 18564801, 30155738, 25658027, 30932294, 31517061, 32236737, 32528171, 33646171, 33726816, 35428369, 32403337, 35207755, 34008892, 37643885, 38112957, 25960145, 25958340, 37937776, 36833224, Hiraide2024[casereport], 41009941)

RYR1 database

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Dec 15, 2024

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 15, 2016

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1: PM3:Strong, PM2:Supporting, PP3, BS2

Apr 29, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 12, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Malignant hyperthermia, susceptibility to, 1

Uncertain:4Benign:2

Mar 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 27, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 20, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1-related disorder

Uncertain:2

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 3933 of the RYR1 protein (p.Tyr3933Cys). This variant is present in population databases (rs147136339, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Tyr3933Cys), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 21674524, 18564801, 20681998, 23558838, 30611313). ClinVar contains an entry for this variant (Variation ID: 133021). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Feb 28, 2023

Undiagnosed Diseases Network, NIH

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

RYR1-related myopathy

Uncertain:2

Apr 11, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change in RYR1 is predicted to replace tyrosine with cysteine at codon 3933, p.(Tyr3933Cys). The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 86. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.13% (172/129,120 alleles) in the European (non-Finnish) population. This variant is almost always reported in a haplotype with two other RYR1 missense variants, p.[(Ile1571Val);(Arg3366His);(Tyr3933Cys)]. The haplotype has been detected in at least 19 individuals with a phenotype consistent with RYR1-related myopathy with/without malignant hyperthermia susceptibility (MHS). Of those individuals, 14 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 8 of those were confirmed in trans by parental/family testing (PMID: 22473935, 23394784, 24950660, 25958340, 25960145, 30611313, 32236737, 35428369). The haplotype segregates with myopathy in a recessive mode of inheritance in at least one family, and there is conflicting evidence for segregation with MHS (PMID: 22473935, 23394784, 25958340). There is limited evidence that the monoallelic haplotype is associated with RYR1-related disease, it has been detected in individuals that unaffected, with MHS, and symptomatic hyperCKaemia (PMID: 25958340, 28259615, 31517061, 32236737). To our knowledge, the variant has not been detected alone. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. The haplotype is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1.

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (PMID: 23919265) (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 31206373). (N) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine (exon 86). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (240 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Tyr3933His) (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Located in the C-terminal/R3 domain (PMID: 23919265). (P) 0705 - No comparable missense variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as VUS (7x), likely benign (1x) and benign (1x) in ClinVar. It has also previously been reported in cis with two additional RYR1 variants (p.(Ile1571Val) and p.(Arg3366His)) in MH susceptible individuals (PMID: 25958340). In addition, these three RYR1 variants have been reported in trans with the pathogenic p.(Val4849Ile) variant in patients with CCD, multiminicore disease, as well as in a patient with core myopathy and MH susceptibility (PMID: 25960145). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Central core myopathy

Uncertain:2

May 05, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

May 05, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.11798A>G (p.Tyr3933Cys) results in a non-conservative amino acid change located in the RyR/IP3R Homology associated domain (IPRIPR013662) of 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 0.00087 in 251418 control chromosomes. c.11798A>G has been reported in the literature in cis with c.10097G>A and c.4711A>G in individuals affected with RYR1-Associated Myopathy (malignant hyperthermia (MH), congenital myopathy, central core disease (CCD), and multi minicore disease (MmD) (examples: Duarte_2011, Rocha_2014, Savarese_2014, Fiszer_2015, Snoeck_2015, Gillies_2015, Kraeva_2015, Garibaldi_2019, Granger_2023). It is unclear if one of the three variants or the combined effect of these mutations are causative for the RYR1-associated diseases in reported individuals. The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 21674524, 25658027, 25960145, 24950660, 25214167, 25735680, 25958340, 36628841, 37937776). ClinVar contains an entry for this variant (Variation ID: 133021). Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Uncertain:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See cases

Uncertain:1

Jul 11, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM3, PP3

Congenital myopathy with fiber type disproportion;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.33

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.9

PhyloP100

9.1

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MVP

1.0

MPC

0.75

ClinPred

0.32

GERP RS

4.1

Varity_R

0.81

gMVP

0.97

Mutation Taster

=2/98

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over