NM_000540.3:c.8026C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_ModeratePP1_Strong

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 2676 of the RYR1 protein, p.(Arg2676Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had 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). Two individuals were reported to have a second variant in RYR1 and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, PMID:16163667, PMID:19191329, PMID:25960145, PMID:21157159, Stowell Laboratory personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in more than ten individuals, PP1_Strong (PMID:30236257, PMID:25960145, PMID:14732627). A REVEL score of 0.601 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024883/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

7
7
4

Clinical Significance

Likely pathogenic reviewed by expert panel P:4U:2O:1

Conservation

PhyloP100: 1.02

Publications

12 publications found
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 Gene-Disease associations (from GenCC):
  • malignant hyperthermia, susceptibility to, 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
  • congenital multicore myopathy with external ophthalmoplegia
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
  • RYR1-related myopathy
    Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
  • central core myopathy
    Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
  • King-Denborough syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • malignant hyperthermia of anesthesia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive centronuclear myopathy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • benign Samaritan congenital myopathy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital myopathy with myasthenic-like onset
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • lethal multiple pterygium syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.8026C>T p.Arg2676Trp missense_variant Exon 50 of 106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.8026C>T p.Arg2676Trp missense_variant Exon 50 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
31
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
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251366
AF XY:
0.00000736
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461890
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152166
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4Uncertain:2Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:2Other:1
-
RYR1 database
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Aug 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 02, 2013
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
Feb 07, 2024
All of Us Research Program, National Institutes of Health
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.8026C>T (p.Arg2676Trp) variant of the RYR1 gene replaces arginine with tryptophan at codon 2676 of the RYR1 protein. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) results (PMID:14732627, 30236257, 16163667, 19191329, 25960145, 21157159). This variant has been identified in an unaffected individual (PMID: 21157159). This variant has been shown to segregate with malignant hyperthermia syndrome (MHS) in more than 10 individuals (PMID: 30236257, 25960145, 14732627). No functional study was identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Computational prediction suggests that this variant may not have deleterious impact on protein structure and function (REVEL score 0.601). Therefore, this c.8026C>T (p.Arg2676Trp) variant of the RYR1 gene is classified as likely pathogenic. -

Jan 20, 2022
MGZ Medical Genetics Center
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

RYR1-related disorder Pathogenic:1
Apr 24, 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 2676 of the RYR1 protein (p.Arg2676Trp). This variant is present in population databases (rs193922826, gnomAD 0.003%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 14732627, 19191329, 25960145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133217). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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 2676 of the RYR1 protein, p.(Arg2676Trp). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000259, a frequency consistent with pathogenicity for MHS. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all of these individuals had 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). Two individuals were reported to have a second variant in RYR1 and were not considered for PS4, PS4_Moderate was applied (PMID:30236257, PMID:16163667, PMID:19191329, PMID:25960145, PMID:21157159, Stowell Laboratory personal communication). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in more than ten individuals, PP1_Strong (PMID:30236257, PMID:25960145, PMID:14732627). A REVEL score of 0.601 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.18
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
.;D
Eigen
Benign
-0.030
Eigen_PC
Benign
-0.18
FATHMM_MKL
Benign
0.29
N
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.0
M;M
PhyloP100
1.0
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-5.7
D;D
REVEL
Uncertain
0.60
Sift
Uncertain
0.021
D;D
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.79
Gain of catalytic residue at L2674 (P = 0.0049);Gain of catalytic residue at L2674 (P = 0.0049);
MVP
0.97
MPC
0.65
ClinPred
0.97
D
GERP RS
2.9
Varity_R
0.26
gMVP
0.87
Mutation Taster
=4/96
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922826; hg19: chr19-38994959; COSMIC: COSV100616767; API