rs193922867

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5_SupportingPP1PS4_ModeratePM1_SupportingPP3_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 arginine with tryptophan at codon 4737 of the RYR1 protein, p.(Arg4737Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five individuals 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), PS4_Moderate (PMID:16163667, 26631338, 30236257, VCEP participating clinical laboratory). This variant segregates with MHS in 4 individuals, PP1 (PMID:26631338, 12208234). 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 >0.85 (.882) supports a pathogenic status for this variant, PP3_Moderate. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4737Gln), PM5_Supporting (PMID:23460944). This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024116/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: 1.31

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 Likely_pathogenic. Variant got 7 ACMG points.

PS4

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

PM1

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

PM5

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.14209C>T	p.Arg4737Trp	missense_variant	Exon 98 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.14209C>T	p.Arg4737Trp	missense_variant	Exon 98 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Jan 03, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 12, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional analysis showed that R4737W increases the probability of the channel opening, resulting in calcium leak and disrupting channel function relative to controls (Kushnir et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 12208234, 16163667, 25960145, 32236737, 20566647, 16835904, 31130284, 27558158, 26631338) -

May 04, 2017

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder

Pathogenic:2

Aug 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 4737 of the RYR1 protein (p.Arg4737Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia (PMID: 12208234, 16163667, 26631338). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg4736Trp. ClinVar contains an entry for this variant (Variation ID: 133060). 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 expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). This variant disrupts the p.Arg4737 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16163667, 18564801, 19648156, 25960145). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A missense variant c.14209C>T, p.(Arg4737Trp) is observed in exon 98 of RYR1 in homozygous state. This variant is reported in the ClinVar database as likely pathogenic (ClinVar id. 133060) and also curated by the ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel (Johnston et al. 2022). In-silico analysis tool REVEL is consistent in predicting this variant to be disease-causing. ACMG classification: Pathogenic Criteria met: PS4_Moderate PM1_Supporting PM5_Supporting PP1 PP3 -

Malignant hyperthermia of anesthesia

Pathogenic:1

Apr 06, 2023

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: Likely 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 arginine with tryptophan at codon 4737 of the RYR1 protein, p.(Arg4737Trp). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five individuals 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), PS4_Moderate (PMID: 16163667, 26631338, 30236257, VCEP participating clinical laboratory). This variant segregates with MHS in 4 individuals, PP1 (PMID:26631338, 12208234). 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 >0.85 (.882) supports a pathogenic status for this variant, PP3_Moderate. Another variant has been assessed as likely pathogenic occurs at this codon, p.(Arg4737Gln), PM5_Supporting (PMID: 23460944). This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1_Supporting, PM5_Supporting, PP1, PP3_moderate. -

Central core myopathy

Pathogenic:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

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

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

.;M

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.65

MutPred

0.84

.;Loss of disorder (P = 0.1177);

MVP

1.0

MPC

0.60

ClinPred

0.94

GERP RS

3.9

Varity_R

0.55

gMVP

0.85

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