rs193922868

Variant names:

• chr19-38577955-G-A
• rs193922868
• NM_000540.3:c.14210G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS4 PM1_Supporting BS2_Supporting PS3_Moderate PP1_Strong 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 arginine with glutamine at codon 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 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), PS4 (PMID:30236257, PMID:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID:21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CV133061/MONDO:0018493/012

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 7.54
• Publications: 10 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: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.14210G>A	p.Arg4737Gln	missense_variant	Exon 98 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14210G>A	p.Arg4737Gln	missense_variant	Exon 98 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251402 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 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: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5 Other:1

Mar 25, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 c.14210G>A; p.Arg4737Gln variant is reported in the literature in several individuals affected with malignant hyperthermia and segregates with disease in families (selected references: Carpenter 2009, Gillies 2008, Knuiman 2019, Miller 2018, Monnier 2005, Robinson 2006). In the majority of cases, a diagnosis of MH was confirmed by a positive in vitro contracture test (IVCT). There is evidence of discordant segregation, which has been observed in at least one phenotype negative/genotype positive individual, and two phenotype positive/genotype negative individuals (Miller 2018). This variant is classified as pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (Variation ID: 133061). Functional studies have indicated that this variant impairs calcium-dependent channel inactivation (Gomez 2016). This variant is also located in a hotspot domain with known pathogenic variants (between residues 4,631 and 4,991), and computational analyses predict that this variant is deleterious (REVEL: 0.89). Based on currently available information this variant is considered to be pathogenic. References: Carpenter D et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009 Oct;103(4):538-48. PMID: 19648156. Gillies RL et al. Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. Anaesth Intensive Care. 2008 May;36(3):391-403. PMID: 18564801. Gomez AC et al. Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation. Am J Physiol Cell Physiol. 2016 Nov 1;311(5):C749-C757. PMID: 27558158 Knuiman GJ et al. The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations. J Neurol. 2019 Apr;266(4):876-887. PMID: 30788618 Miller DM et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018 Oct;121(4):944-952. PMID: 30236257 Monnier N et al. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat. 2005 Nov;26(5):413-25. PMID: 16163667. Robinson R et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. PMID: 16917943. -

Nov 16, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM1, PM2, PM5 -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 27558158); Previously reported in association with malignant hyperthermia in multiple unrelated individuals, with some reports using alternate nomenclature R4893Q (PMID: 16163667, 16917943, 18564801, 19648156, 30236257); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16917943, 25960145, 27663056, 28326467, 16163667, 30788618, 19648156, 30236257, 18564801, 20681998, 33767344, 37154182, 27558158) -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:4

Feb 07, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been observed in more than 10 individuals with personal or family history of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 16163667, 18564801, 19648156, 25960145). This variant segregates with malignant hyperthermia syndrome (MHS) in more than 6 meioses (PMID:30236257, 18564801). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified. This variant is located at a mutational hot spot region that contributes to MHS (PMID: 21118704). Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). Computational prediction (REVEL=0.89 PMID: 27666373) suggests that this variant may have deleterious impact on protein structure and function. Alteration affecting the same amino acid, c.14209C>T (p.Arg4737Trp), was classified as likely pathogenic by the expert panel (ClinVar ID:133060). Therefore, this c.14210G>A (p.Arg4737Gln) variant of RYR1 gene is classified as pathogenic. -

Sep 20, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders (OMIM). Gain of function mechanism has been described in the context of malignant hyperthermia susceptibility 1 (MIM#145600) and autosomal dominant congenital myopathy 1A with susceptibility to malignant hyperthermia (MIM#117000). Autosomal recessive congenital myopathy 1B (MIM#255320) is associated with a loss of function mechanism (PMIDs: 27855725, 23919265). The mechanism of King-Denborough syndrome (MIM#619542) is unclear. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.(Arg4737Trp): 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is within one of the three enriched hotspot regions enriched for autosomal dominant RYR1 variants (PMID: 33767344). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg4737Trp) variant has been classified as likely pathogenic for malignant hyperthermia susceptibility (MHS) by an expert panel (ClinVar) and by the European Malignant Hyperthermia Group. (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic for malignant hyperthermia susceptibility (MHS) by an expert panel (ClinVar). It should also be noted that this variant has been classified as likely pathogenic by the European Malignant Hyperthermia Group. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces arginine with glutamine at codon 4737 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is located in a region of the RYR1 protein considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). A functional study has shown the mutant protein to exhibit hypersensitivity to an RYR1 agonist in calcium release assays (PMID: 36208971). This variant has been reported in over ten unrelated individuals affected with malignant hyperthermia susceptibility (PMID: 16163667, 18564801, 24433488, 30236257, 36208971). This variant has been shown to segregate with malignant hyperthermia susceptibility in 6 meioses in one family (PMID:18564801) and reported to segregate with disease in additional families (PMID: 30236257). Two related individuals who carry this variant have been reported to test negative in in vitro contracture tests (PMID: 30236257). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg4737Trp, is known to be associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133060), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Pathogenic. -

May 20, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

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 arginine with glutamine at codon 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 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), PS4 (PMID:30236257, PMID:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate. -

RYR1-related disorder Pathogenic:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). This variant is present in population databases (rs193922868, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). 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. ClinVar contains an entry for this variant (Variation ID: 133061). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16163667, 18564801, 19648156, 25960145). -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1

Jul 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	.;M
PhyloP100		7.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.10	T;T
Polyphen		1.0	D;D
Vest4		0.36
MutPred		0.82		.;Gain of phosphorylation at Y4733 (P = 0.2103);
MVP		1.0
MPC		0.66
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.79
Mutation Taster		=15/85	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: rs193922868; hg19: chr19-39068595;