GeneBe

19-38496283-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 15P and 4B. PM1_SupportingPS4PS3_ModerateBS2PM5PP3_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 threonine with methionine at codon 2206 of the RYR1 protein, p.(Thr2206Met). 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 67 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 63 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), PS4 (PMID:30236257, 12059893, 24433488, 23558838, 10484775, 25735680, 25960145, 16163667, 11575529, 12220451, 12434264, 15731587, 17081152, 18505122, 22696611, 9497245, 25268394, 31559918). This variant has been identified in at least three individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:27586648). An ex vivo assay in patient derived myotubes from two related individuals showed an increased sensitivity to RYR1 agonists (PMID:12220451). 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 PM5 (PMID:21118704). Another variant that has been assessed as pathogenic occurs at this codon, p.(Thr2206Arg), PM5. This variant segregates with MHS in nine individuals, PP1_Strong (PMID:12059893, 25960145). A REVEL score >0.85 (0.95) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). Criteria implemented: PS4, PS3_Moderate, PM1_Supporting, PM5, PP1_Strong, PP3_Moderate, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024622/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

15
3

Clinical Significance

Pathogenic reviewed by expert panel P:25O:2

Conservation

PhyloP100: 7.91

Publications

41 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: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • RYR1-related myopathy
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
  • congenital multicore myopathy with external ophthalmoplegia
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
  • central core myopathy
    Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • 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

new If you want to explore the variant's impact on the transcript NM_000540.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

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.
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.
BS2
For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
RYR1
NM_000540.3
MANE Select
c.6617C>Tp.Thr2206Met
missense
Exon 40 of 106NP_000531.2P21817-1
RYR1
NM_001042723.2
c.6617C>Tp.Thr2206Met
missense
Exon 40 of 105NP_001036188.1P21817-2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
RYR1
ENST00000359596.8
TSL:5 MANE Select
c.6617C>Tp.Thr2206Met
missense
Exon 40 of 106ENSP00000352608.2P21817-1
RYR1
ENST00000355481.8
TSL:1
c.6617C>Tp.Thr2206Met
missense
Exon 40 of 105ENSP00000347667.3P21817-2
RYR1
ENST00000594335.6
TSL:1
n.6617C>T
non_coding_transcript_exon
Exon 40 of 103ENSP00000470927.2M0R014

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251224
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461714
Hom.:
0
Cov.:
32
AF XY:
0.0000165
AC XY:
12
AN XY:
727144
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53246
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000225
AC:
25
AN:
1112012
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
2
4
6
8
10
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:
0.0000394
AC:
6
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74322
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.0000518
Hom.:
0
Bravo
AF:
0.0000302
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
10
-
-
Malignant hyperthermia, susceptibility to, 1 (11)
6
-
-
not provided (7)
2
-
-
Malignant hyperthermia of anesthesia (2)
1
-
-
Inborn genetic diseases (1)
1
-
-
King Denborough syndrome (1)
1
-
-
King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy (1)
1
-
-
King Denborough syndrome;C5830701:Central core myopathy (1)
1
-
-
Malignant hyperthermia, susceptibility to (1)
1
-
-
Ptosis;C0344490:Absence of the sacrum;na:History of neonatal hypotonia (1)
1
-
-
RYR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.5
M
PhyloP100
7.9
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.2
D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D
Varity_R
0.72
gMVP
0.87
Mutation Taster
=0/100
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

Other links and lift over

dbSNP: rs118192177;
hg19: chr19-38986923;
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