rs4802584

Positions:

chr19-38534726-C-G

Variant summary

Our verdict is Benign. Variant got -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

Scores

Clinical Significance

Benign reviewed by expert panel B:18O:1

Conservation

PhyloP100: 8.16

Variant links:

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 links:

RYR1 (HGNC:):

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.11266C>G	p.Gln3756Glu	missense_variant	79/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.11266C>G	p.Gln3756Glu	missense_variant	79/106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3452

AN:

152162

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0345

AC:

8651

AN:

250408

Hom.:

300

AF XY:

0.0318

AC XY:

4311

AN XY:

135396

show subpopulations

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 SAS exome

AF:

0.0302

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.:

AF XY:

0.0226

AC XY:

16409

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.00633

Gnomad4 AMR exome

AF:

0.108

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0686

Gnomad4 SAS exome

AF:

0.0286

Gnomad4 FIN exome

AF:

0.0442

Gnomad4 NFE exome

AF:

0.0172

Gnomad4 OTH exome

AF:

0.0258

GnomAD4 genome

AF:

0.0227

AC:

3455

AN:

152280

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1891

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00772

Gnomad4 AMR

AF:

0.0728

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0596

Gnomad4 SAS

AF:

0.0327

Gnomad4 FIN

AF:

0.0445

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0239

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00590

AC:

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:18Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Malignant hyperthermia, susceptibility to, 1

Benign:5

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Benign, reviewed by expert panel	curation	ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	Mar 17, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

not provided

Benign:3Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Central core myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.0052

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.29

.;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.5

.;N;.

PrimateAI

Uncertain

0.64

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

GERP RS

4.8

Varity_R

0.054

gMVP

0.074

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over