rs193922839

Variant names:

• chr19-38534775-G-A
• rs193922839
• NM_000540.3:c.11315G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-38534775-G-A
• chr19-38534775-G-C
• chr19-38534775-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS4_Moderate BS2_Supporting PP3_Moderate PP1_Strong

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 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven 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), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID:30236257). 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 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023909/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:12 U:1 O:1
• Conservation: PhyloP100: 10.0
• Publications: 11 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: 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.11315G>A	p.Arg3772Gln	missense_variant	Exon 79 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.11315G>A	p.Arg3772Gln	missense_variant	Exon 79 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249946 AF XY: 0.00000739

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: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461422 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726958

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:4

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals with malignant hyperthermia susceptibility (PMID: 19645060, 30236257, 17483490, 22473935, 23553787, 35849058). This variant is present in 5/281314 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in seven affected individuals (PMID: 19645060, 22473935). This variant is predicted to be deleterious by in silico analysis. -

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Likely 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 3772 of the RYR1 protein, p.(Arg3772Gln). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000033, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, seven 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), however, three of these individuals were homozygous for this variant and were not considered for PS4, PS4_Moderate was applied (PMID: 30236257, 17483490). This variant segregates with MHS in at least seven individuals, PP1_Strong (PMID:19645060, 22473935). This variant has been identified in an individual with a negative IVCT/CHCT result. BS2_Moderate (PMID: 30236257). 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 (0.888) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate, BS2_Moderate. -

Oct 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PP1_STR,PS4_MOD,PP3_MOD,BS2_MOD -

Jul 07, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 variant c.11315G>A causes an amino acid change from Arg to Gln at position 3772 in exon no. 79 of 106. This variant has been observed in the heterozygous state in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 19645060, 22473935, 30236257, 17483490).It is classified as pathogenic for autosomal recessive congenital myopathy 1B whereas it is classified as likely pathogenic for autosomal dominant malignant hyperthermia susceptibility according to the recommendations of ACMG/AMP/ClinGen SVI guidelines. -

not provided Pathogenic:3 Other:1

Dec 16, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 30236257, 23919265, 19191329, 18253926, 21911697, 21795085, 23553787, 23394784, 27447704, 27377473, 23069638, 31447099, 24091937, 21062345, 30689883, 22473935, 19645060, 17483490, 34106991) -

RYR1-related disorder Pathogenic:2

Aug 31, 2024

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 3772 of the RYR1 protein (p.Arg3772Gln). This variant is present in population databases (rs193922839, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive RYR1-related myopathy and malignant hyperthermia susceptibility (PMID: 17483490, 19645060). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133012). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg3772 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19191329, 21062345, 23919265, 24091937). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 24, 2024

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

The c.11315G>A (p.Arg3772Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous change in individuals with malignant hyperthermia (PMID: 19645060, 30236257) and as a homozygous and compound heterozygous change in individuals with RYR1-related myopathies (PMID: 17483490, 19645060, 23553787, 18253926). A different amino acid change at the same residue (p.Arg3772Gln) have been previously reported in individuals with malignant hyperthermia and RYR1-related myopathy (PMID: 19191329, 21795085, 23919265, 24091937, 30611313). It is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0004% (7/1613530) and thus is presumed to be rare. Based on the available evidence, the c.11315G>A (p.Arg3772Gln) variant is classified as Pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1

May 30, 2025

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the homozygous and compound heterozygous states in several individuals with autosomal recessive RYR1-related myopathy (see for examples: Zhou et al. 2007. PubMed ID: 17483490; Carpenter et al. 2009. PubMed ID: 19645060; Stehlíková et al. 2016. PubMed ID: 27447704; Maggi et al. 2013. PubMed ID: 23394784; Babić Božović et al. 2021. PubMed ID: 34106991). Carriers of this variant have also been reported to be susceptible to malignant hyperthermia (Zhou et al. 2007. PubMed ID: 17483490; Carpenter et al. 2009. PubMed ID: 19645060; Miller et al. 2018. PubMed ID: 30236257). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant has been classified as likely pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/133012/). A different missense change impacting the same amino acid (p.Arg3772Trp) has also been reported in individuals with malignant hyperthermia and autosomal recessive congenital myopathy (Levano et al. 2009. PubMed ID: 19191329; Bevilacqua et al. 2011. PubMed ID: 21062345). Given the evidence, we classify the c.11315G>A (p.Arg3772Gln) variant as pathogenic for autosomal recessive and dominant RYR1-related disorders. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org). -

Inborn genetic diseases Pathogenic:1

May 05, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11315G>A (p.R3772Q) alteration is located in exon 79 (coding exon 79) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 11315, causing the arginine (R) at amino acid position 3772 to be replaced by a glutamine (Q)._x000D_ _x000D_ Based on the available evidence, the RYR1 c.11315G>A (p.R3772Q) alteration is classified as likely pathogenic for autosomal dominant malignant hyperthermia susceptibility (MHS) and autosomal recessive RYR1-related myopathy; however, its clinical significance for autosomal dominant RYR1-related myopathy is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/281314) total alleles studied. This variant has been reported in multiple unrelated individuals who had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT), or who have a personal or family history of a malignant hyperthermia reaction (Zhou, 2007; Carpenter, 2009; Klein, 2012; Miller, 2018). In addition, this alteration has been observed in the homozygous or compound heterozygous state in multiple individuals with myopathy (Zhou, 2007; Monnier, 2008; Carpenter, 2009; Klein, 2012; Hwang, 2012; Maggi, 2013; Stehlíková, 2017; Miller, 2018; Babi Boovi, 2021). This variant has been observed to segregate with autosomal dominant malignant hyperthermia susceptibility (MHS) and/or autosomal recessive myopathy in multiple families (Carpenter, 2009; Klein, 2012). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Malignant hyperthermia of anesthesia;C0027868:Neuromuscular disease Pathogenic:1

Nov 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3772Gln variant in RYR1 has been reported in the heterozygous state in 1 individual with a malignant hyperthermia susceptibility (MHS) phenotype (Carpe nter 2009) and in the homozygous or compound heterozygous state in at least 10 i ndividuals with congenital myopathy (Zhou 2007, Monnier 2008, Carpenter 2009, Kl ein 2012). Three of the individuals with congenital myopathy also have a MHS phe notype (Zhou 2007, Carpenter 2009, Klein 2012). This variant segregated with mal ignant hyperthermia in 9 affected relatives (8 heterozygotes and 1 homozygote) f rom 3 families (Carpenter 2009, Klein 2012) and with congenital myopathy in the homozygous or compound heterozygous state in 6 affected relatives from 3 familie s, 3 of whom who also had MH (Zhou 2007, Carpenter 2009, Klein 2012). mRNA expr ession studies from muscle biopsies of patients homozygous for the p.Arg3772Gln variant provide some evidence that it causes decreased mRNA expression (Zhou et al. 2013. This variant has been reported by other clinical laboratories in ClinV ar (Variation ID 133012) and has been identified in 2/11052 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs193922839). In summary, the p.Arg3772Gln variant meets criteria to be cla ssified as pathogenic for malignant hyperthermia in an autosomal dominant manner and congenital myopathy in an autosomal recessive manner based upon presence in multiple affected individuals, segregation studies, very low frequency in the g eneral population and functional studies. -

Scoliosis;C0221629:Proximal muscle weakness;C0427064:Pelvic girdle muscle weakness;C1836609:Progressive distal muscle weakness;C1837658:Delayed gross motor development Uncertain:1

Aug 29, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	.;M;.;.
PhyloP100		10
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D;D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.62
MutPred		0.77		.;Loss of MoRF binding (P = 0.0177);.;.;
MVP		1.0
MPC		0.69
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.36
Mutation Taster		=2/98	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: rs193922839; hg19: chr19-39025415;