19-38446710-G-C

Variant names:

• chr19-38446710-G-C
• rs1801086
• NM_000540.3:c.742G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PS4_Moderate PM1_Supporting PP1_Moderate PS3_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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID:21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024799/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 7.59
• Publications: 26 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 13 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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.

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.742G>C	p.Gly248Arg	missense	Exon 9 of 106	NP_000531.2
	RYR1	NM_001042723.2		c.742G>C	p.Gly248Arg	missense	Exon 9 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.742G>C	p.Gly248Arg	missense	Exon 9 of 106	ENSP00000352608.2
	RYR1	ENST00000355481.8	TSL:1	c.742G>C	p.Gly248Arg	missense	Exon 9 of 105	ENSP00000347667.3
	RYR1	ENST00000594335.6	TSL:1	n.742G>C		non_coding_transcript_exon	Exon 9 of 103	ENSP00000470927.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251188 AF XY: 0.00000737

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111900

Other (OTH) AF: 0.0000497 AC: 3 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

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

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:5

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 248 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies in HEK293 cells have shown that cells expressing this variant have increased sensitivity to caffeine, halothane, and 4-CmC compared to cells expressing wild-type RYR1 (PMID: 15448513, 20461000, 27857962, 9334205). This variant has been reported in families and individuals affected with malignant hyperthermia susceptibility (PMID: 18564801, 19346234, 23558838, 30236257). This variant has been shown to segregate with disease in 1 family, this family carried a second RYR1 variant of uncertain significance in cis (PMID: 19346234, 30236257). This variant has been identified in 4/282572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Sep 08, 2022

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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate.

Nov 03, 2022

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 10 heterozygote(s), 0 homozygote(s)). An alternative nucleotide change that results in the same amino acid change is also present in gnomAD <0.01 (v4: 5 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (ClinVar). Additional information: Variant is predicted to result in a missense amino acid change from glycine to arginine; This gene is associated with both recessive and dominant disease (OMIM); 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.

not provided Pathogenic:4 Other:1

May 30, 2024

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: 7849712, 31301762, 32231684, 20461000, 23422674, 25525159, 24627108, 19346234, 27147545, 9334205, 9873004, 33564012, 26115329, 6917943, 15448513, 33767344, 27857962, 23919265, 23558838, 12565913, 11575529, 36245440, 21795085, 30236257, 18564801)

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 19, 2013

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PM1:Strong, PS1, PS3:Moderate, PP1, PS4:Supporting

Feb 04, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 c.742G>C; p.Gly248Arg variant (rs1801086) is published in the literature in several individuals affected with malignant hyperthermia (MH), confirmed by caffeine/halothane contracture test (Brandom 2013, Gillies 2008, Sambuughin 2001, Sei 2004) and is considered diagnostic for MH by the European Malignant Hyperthermia group. The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 133203) and is only found on 4 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). In support of this prediction, functional studies show variants in this region cause hyperactive RYR1 channels (Tong 1997). Based on available information, this variant is classified as pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-86. 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. Sambuughin N et al. North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology. 2001 Sep;95(3):594-9. Sei Y et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology. 2004 Oct;101(4):824-30. Tong J et al. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997 Oct 17;272(42):26332-9.

Autism spectrum disorder due to AUTS2 deficiency Pathogenic:1

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

RYR1-related disorder Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is present in population databases (rs1801086, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 133203). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 6917943, 9334205, 9873004, 12565913, 23919265, 27857962). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.93		Gain of solvent accessibility (P = 0.0171)
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.63
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs1801086; hg19: chr19-38937350;