rs4802584

Variant names:

• chr19-38534726-C-G
• rs4802584
• NM_000540.3:c.11266C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

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 Glutamine with Glutamic Acid at codon 3756 of the RYR1 protein, p.(Gln3756Glu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.1085, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023907/MONDO:0007783/012

• Frequency:
  • Genomes: 𝑓 0.023 (93 hom., cov: 31)
  • Exomes 𝑓: 0.023 (729 hom.)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Benign reviewed by expert panel B:18 O:1
• Conservation: PhyloP100: 8.16
• Publications: 22 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: Benign. The variant received -8 ACMG points.

• BA1: 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.11266C>G	p.Gln3756Glu	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.11266C>G	p.Gln3756Glu	missense_variant	Exon 79 of 106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3452 AN: 152162 Hom.: 92 Cov.: 31

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0596

Gnomad SAS AF: 0.0327

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0345 AC: 8651 AN: 250408 AF XY: 0.0318

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0475

Gnomad FIN exome AF: 0.0448

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0228 AC: 33386 AN: 1461400 Hom.: 729 Cov.: 32 AF XY: 0.0226 AC XY: 16409 AN XY: 726938

African (AFR) AF: 0.00633 AC: 212 AN: 33476

American (AMR) AF: 0.108 AC: 4838 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26116

East Asian (EAS) AF: 0.0686 AC: 2720 AN: 39678

South Asian (SAS) AF: 0.0286 AC: 2466 AN: 86146

European-Finnish (FIN) AF: 0.0442 AC: 2360 AN: 53398

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.0172 AC: 19128 AN: 1111822

Other (OTH) AF: 0.0258 AC: 1555 AN: 60378

GnomAD4 genome AF: 0.0227 AC: 3455 AN: 152280 Hom.: 93 Cov.: 31 AF XY: 0.0254 AC XY: 1891 AN XY: 74452

African (AFR) AF: 0.00772 AC: 321 AN: 41562

American (AMR) AF: 0.0728 AC: 1113 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.0596 AC: 308 AN: 5170

South Asian (SAS) AF: 0.0327 AC: 158 AN: 4826

European-Finnish (FIN) AF: 0.0445 AC: 472 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1026 AN: 68020

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.0178 Hom.: 34

Bravo AF: 0.0239

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0314 AC: 3818

Asia WGS AF: 0.0570 AC: 198 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

Apr 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 06, 2018

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Benign:5

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2021

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Benign

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 Glutamine with Glutamic Acid at codon 3756 of the RYR1 protein, p.(Gln3756Glu). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.1085, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. -

Sep 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:3 Other:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital multicore myopathy with external ophthalmoplegia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

RYR1-related disorder Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.0052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.29	.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.5	.;N;.
PhyloP100		8.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	2.4	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	.;.;T
Polyphen		0.0	B;B;.
Vest4		0.058
MPC		0.62
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.074
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs4802584; hg19: chr19-39025366; COSMIC: COSV62093128; COSMIC: COSV62093128;