rs193922860

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM1_Supporting

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 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID:16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID:21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024086/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:11O:1

Conservation

PhyloP100: 2.91

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

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.13934G>A	p.Arg4645Gln	missense_variant	95/106	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.13934G>A	p.Arg4645Gln	missense_variant	95/106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

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

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251466

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000251

AC:

367

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

175

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00831

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces arginine with glutamine at codon 4645 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 two individuals who experienced malignant hyperthermia episode, one of whom had another pathogenic variant in the same gene (PMID: 16732084). This variant has been identified in 15/251466 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. -

not provided

Uncertain:2Other:1

not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	Identified as heterozygous in an individual with neuroleptic malignant syndrome, however it was also identified in multiple control samples (Sato et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21918424, 19223216, 16917943, 21878807, 23476141, 19931341, 16732084) -

RYR1-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4645 of the RYR1 protein (p.Arg4645Gln). This variant is present in population databases (rs193922860, gnomAD 0.04%). This missense change has been observed in individual(s) with neuroleptic malignant syndrome and malignant hyperthermia or suspected malignant hyperthermia (PMID: 16732084, 16917943, 19223216, 19931341). ClinVar contains an entry for this variant (Variation ID: 133053). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 07, 2023	The RYR1 c.13934G>A variant is predicted to result in the amino acid substitution p.Arg4645Gln. This variant has been reported in individuals with malignant hyperthermia (Table S1, Robinson et al. 2006. PubMed ID: 16917943) and in another individual with suspected neuroleptic malignant syndrome (Sato et al. 2010. PubMed ID: 19931341). It was also reported in the compound heterozygous state with another RYR1 variant in an individual who was a victim of heat stroke who was thought to experience stress induced malignant hyperthermia (Nishio et al. 2009. PubMed ID: 19223216; Carsana et al. 2013. PubMed ID: 23476141). This variant was also reported in study of hypermobility spectrum disorder in ballet professionals (Appendix Table A1, Vera et al. 2020. PubMed ID: 31765226:). This variant has also been found in control populations (Sato et al. 2010. PubMed ID: 19931341) and is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-39062846-G-A). Of note, this variant has been reviewed by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel and was determined to be a variant of uncertain significance for malignant hyperthermia susceptibility (https://www.ncbi.nlm.nih.gov/clinvar/variation/133053/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 paper in HGMD in an unspecified number of malignant hyperthermia patients (classified as DM). This variant is present in ClinVar with no interpretation. The variant has a Max MAF of 0.03% in ExAC (3 East Asian alleles) and 0.04% in gnomAD (7 East Asian alleles). 3 non-mammals have a Gln at this position. -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant hyperthermia of anesthesia

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Apr 06, 2023

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 4645 of the RYR1 protein, p.(Arg4645Gln). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00038, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, neither of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result. Additionally, one of these individuals had a second variant in RYR1, p.(Arg2435His) that is classified as pathogenic, PS4 was not implemented (PMID: 16732084). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score of 0.567 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting. -

Central core myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

.;D

Eigen

Benign

0.037

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.068

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.57

Sift

Benign

0.078

T;T

Polyphen

0.043

B;B

Vest4

0.60

MutPred

0.91

.;Gain of catalytic residue at R4645 (P = 0.1258);

MVP

0.99

MPC

0.66

ClinPred

0.035

GERP RS

5.1

Varity_R

0.081

gMVP

0.62

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