rs118192158

Variant names:

• chr19-38585952-G-A
• rs118192158
• NM_000540.3:c.14818G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38585952-G-A
• chr19-38585952-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1_Supporting PS4_Moderate PP3_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 alanine with threonine at codon 4940 of the RYR1 protein, p.(Ala4940Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been identified in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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), PS4_Moderate (PMID:15731587, personal communication from VCEP laboratory). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). A REVEL score >0.85 (0.882) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024266/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:11 U:2 O:1
• Conservation: PhyloP100: 9.99
• Publications: 21 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.14818G>A	p.Ala4940Thr	missense	Exon 103 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.14803G>A	p.Ala4935Thr	missense	Exon 102 of 105	NP_001036188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.14818G>A	p.Ala4940Thr	missense	Exon 103 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.14803G>A	p.Ala4935Thr	missense	Exon 102 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.*5528G>A		non_coding_transcript_exon	Exon 100 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74224

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000186 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:11 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7 Other:1

Mar 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also reported in a patient with malignant hyperthermia susceptibility (Sambuughin et al., 2005); Published functional studies using transgenic C. elegans with the A4940T variant demonstrate a damaging effect of increased sensitivity to halothane and caffeine, with decreased locomotion (Nicoll Baines et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14670767, 23558838, 12565913, 20301565, 15731587, 12467748, 28325813, 25747005, 23183335, 28687594, 16084090, 1256913, 31321302, 31395954, 31559918, 32403337, 33646171)

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 22, 2018

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 27, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 08, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_M, PM1, PM2, PP1, PP3, PP4

RYR1-related disorder Pathogenic:2

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with Central Core Disease (MIM: #117000; PMID: 32403337, 31321302, 30155738, 14670767), and as a compound heterozygous change in patients with congenital myopathy (PMID: 30155738, 31395954). Functional studies in cells have shown that the c.14818G>A (p.Ala4940Thr) variant significantly reduces the threshold for spontaneous Ca2+ release during store Ca2+ overload (SOICR), which causes uncontrolled muscle contraction (PMID: 28687594). It is absent from the gnomAD population database and thus is presumed to be rare. The c.14818G>A (p.Ala4940Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.14818G>A (p.Ala4940Thr) variant is classified as Pathogenic.

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4940 of the RYR1 protein (p.Ala4940Thr). This variant is present in population databases (rs118192158, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant central core disease (PMID: 1256913, 12467748, 14670767, 15731587, 23183335, 23558838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65927). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RYR1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Malignant hyperthermia of anesthesia Pathogenic:1

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala4940Thr variant in RYR1 has been previously reported in at least 5 heterozygous individuals with central core disease or RYR1-related myopathy, and segregated in 5 affected relatives (Kraeva 2013 PMID 23183335, Todd 2018 PMID 30155738, Kushnir 2020 PMID 32236737, Davis 2003 PMID 12565913, Quinlivan 2003 PMID 14670767). It has also been reported in at least 1 individual with malignant hyperthermia (MH) susceptibility (Brandom 2013 PMID 23558838, Sambuughin PMID 15731587) and in 1 compound heterozygous individual with myopathy (Todd 2018 PMID 30155738). This variant was absent from large population studies, but has been reported in ClinVar (Variation ID 65927). In vitro evidence in transfected HEK293 cells indicates that this variant affects protien function (Chen 2017 PMID 28687594). In addition, a transgenic C. elegan model with the Ala4940Thr variant showed increased sensitivity to halothane and caffeine and decreased locomotion (Baines 2017 PMID 28325813). Lastly, in a study performed in muscle tissue from patients carrying the Ala4940Thr variant, RYR1 was co-immunoprecipitated with calstabin1, which binds to RYR1 and stabilizes the closed state of the calcium channel. Reduced RYR1-calstabin1 was observed relative to controls, which suggests that the variant results in a leaky RYR1 calcium channel (Kushnir 2020 PMID 32236737). Computational prediction tools and conservation analyses suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant central core disease but has also been reported in MH susceptibility. ACMG/AMP criteria applied: PM2, PS4_Moderate, PP1_Moderate, PP3, PS3_Moderate.

Central core myopathy Pathogenic:1

May 11, 2010

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Aug 01, 2025

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

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 alanine with threonine at codon 4940 of the RYR1 protein, p.(Ala4940Thr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been identified in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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), PS4_Moderate (PMID:15731587, personal communication from VCEP laboratory). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.882) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1_Supporting, PP3_Moderate.

See cases Uncertain:1

Mar 08, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP3

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Benign	0.86
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.98	L
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.85		Gain of disorder (P = 0.16)
MVP		0.95
MPC		0.55
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.79
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118192158; hg19: chr19-39076592;