19-38543551-A-G

Variant names:

• chr19-38543551-A-G
• rs147136339
• NM_000540.3:c.11798A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21 B:2 O:1
• Conservation: PhyloP100: 9.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.11798A>G	p.Tyr3933Cys	missense_variant	Exon 86 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.11798A>G	p.Tyr3933Cys	missense_variant	Exon 86 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152094 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000867 AC: 218 AN: 251418 Hom.: 0 AF XY: 0.000949 AC XY: 129 AN XY: 135908

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 SAS exome AF: 0.000621

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.: 3 Cov.: 37 AF XY: 0.00122 AC XY: 886 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74432

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00137 Hom.: 1

Bravo AF: 0.00102

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Other:1

Aug 15, 2016

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 12, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2022

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

- -

Apr 29, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 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, Hiraide2024[casereport], 37937776, 36833224) -

Malignant hyperthermia, susceptibility to, 1 Uncertain:4 Benign:2

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 27, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

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

- -

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 20, 2024

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MVP		1.0
MPC		0.75
ClinPred		0.32	T
GERP RS		4.1
Varity_R		0.81
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs147136339; hg19: chr19-39034191; COSMIC: COSV62113208; COSMIC: COSV62113208;