19-38446710-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP1_ModeratePS3_ModeratePS1PS4_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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID:21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024799/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 7.59

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 Pathogenic. Variant got 13 ACMG points.

PS1

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

PS3

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

PS4

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

PM1

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.742G>C	p.Gly248Arg	missense_variant	Exon 9 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.742G>C	p.Gly248Arg	missense_variant	Exon 9 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.742G>C	p.Gly248Arg	missense_variant	Exon 9 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.742G>C		non_coding_transcript_exon_variant	Exon 9 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251188

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727154

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Nov 19, 2013

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RYR1 c.742G>C; p.Gly248Arg variant (rs1801086) is published in the literature in several individuals affected with malignant hyperthermia (MH), confirmed by caffeine/halothane contracture test (Brandom 2013, Gillies 2008, Sambuughin 2001, Sei 2004) and is considered diagnostic for MH by the European Malignant Hyperthermia group. The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 133203) and is only found on 4 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). In support of this prediction, functional studies show variants in this region cause hyperactive RYR1 channels (Tong 1997). Based on available information, this variant is classified as pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-86. Gillies RL et al. Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. Anaesth Intensive Care. 2008 May;36(3):391-403. Sambuughin N et al. North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology. 2001 Sep;95(3):594-9. Sei Y et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology. 2004 Oct;101(4):824-30. Tong J et al. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997 Oct 17;272(42):26332-9. -

RYR1 database

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RYR1: PM1:Strong, PS1, PS3:Moderate, PP1, PS4:Supporting -

May 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7849712, 31301762, 32231684, 20461000, 23422674, 25525159, 24627108, 19346234, 27147545, 9334205, 9873004, 33564012, 26115329, 6917943, 15448513, 33767344, 27857962, 23919265, 23558838, 12565913, 11575529, 36245440, 21795085, 30236257, 18564801) -

Malignant hyperthermia, susceptibility to, 1

Pathogenic:4

Nov 03, 2022

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Moderate+PS4_Moderate+PP1_Moderate+PM1+PS3_Moderate -

Sep 08, 2022

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Significance: 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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate. -

Sep 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 248 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies in HEK293 cells have shown that cells expressing this variant have increased sensitivity to caffeine, halothane, and 4-CmC compared to cells expressing wild-type RYR1 (PMID: 15448513, 20461000, 27857962, 9334205). This variant has been reported in families and individuals affected with malignant hyperthermia susceptibility (PMID: 18564801, 19346234, 23558838, 30236257). This variant has been shown to segregate with disease in 1 family, this family carried a second RYR1 variant of uncertain significance in cis (PMID: 19346234, 30236257). This variant has been identified in 4/282572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Autism spectrum disorder due to AUTS2 deficiency

Pathogenic:1

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

RYR1-related disorder

Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is present in population databases (rs1801086, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 133203). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 6917943, 9334205, 9873004, 12565913, 23919265, 27857962). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.81

MutPred

0.93

Gain of solvent accessibility (P = 0.0171);Gain of solvent accessibility (P = 0.0171);

MVP

0.98

MPC

1.1

ClinPred

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.63

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