NM_000540.3:c.2654G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

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 histidine at codon 885 of the RYR1 protein (p.Arg885His). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00042, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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, the MAF in the SAS population in gnomAD does not allow PS4 to be utilized (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 of 0.609 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. LINK:https://erepo.genome.network/evrepo/ui/classification/CA063661/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:13B:2

Conservation

PhyloP100: 2.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.2654G>A	p.Arg885His	missense_variant	Exon 21 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.2654G>A	p.Arg885His	missense_variant	Exon 21 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.2654G>A	p.Arg885His	missense_variant	Exon 21 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.2654G>A		non_coding_transcript_exon_variant	Exon 21 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

249460

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

135060

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000191

AC:

279

AN:

1460650

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000151

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000938

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:13Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:4

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

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 histidine at codon 885 of the RYR1 protein (p.Arg885His). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00042, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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, the MAF in the SAS population in gnomAD does not allow PS4 to be utilized (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 of 0.609 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: none. -

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 885 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 46/280838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 01, 2013

Arcensus

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:3

Jul 14, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported as heterozygous in an adult male with central core disease and his mildly symptomatic father (Snoeck et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25960145, 34426522) -

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:2

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Myopathy

Pathogenic:1

Jun 18, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder

Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 885 of the RYR1 protein (p.Arg885His). This variant is present in population databases (rs370634440, gnomAD 0.04%). This missense change has been observed in individual(s) with central core disease (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 212100). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Uncertain:1

Oct 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy, RYR1-associated

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Central core myopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

.;D

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.40

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.70

MVP

1.0

MPC

1.1

ClinPred

0.30

GERP RS

4.0

Varity_R

0.40

gMVP

0.76

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

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