chr19-38566986-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024057/MONDO:0007783/012

Frequency

Genomes: 𝑓 0.0033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0056 ( 23 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

6
8
4
Splicing: ADA: 0.002327
2

Clinical Significance

Benign reviewed by expert panel U:3B:19O:1

Conservation

PhyloP100: 2.97
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkc.13513G>C p.Asp4505His missense_variant 92/106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.13513G>C p.Asp4505His missense_variant 92/1065 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
AF:
0.00332
AC:
505
AN:
152106
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00123
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00190
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00123
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00562
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00337
AC:
696
AN:
206260
Hom.:
2
AF XY:
0.00361
AC XY:
400
AN XY:
110706
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00130
Gnomad ASJ exome
AF:
0.00422
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00266
Gnomad FIN exome
AF:
0.00181
Gnomad NFE exome
AF:
0.00545
Gnomad OTH exome
AF:
0.00287
GnomAD4 exome
AF:
0.00556
AC:
8003
AN:
1438904
Hom.:
23
Cov.:
32
AF XY:
0.00547
AC XY:
3901
AN XY:
713364
show subpopulations
Gnomad4 AFR exome
AF:
0.000906
Gnomad4 AMR exome
AF:
0.00148
Gnomad4 ASJ exome
AF:
0.00471
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00267
Gnomad4 FIN exome
AF:
0.00164
Gnomad4 NFE exome
AF:
0.00655
Gnomad4 OTH exome
AF:
0.00452
GnomAD4 genome
AF:
0.00332
AC:
505
AN:
152224
Hom.:
0
Cov.:
31
AF XY:
0.00321
AC XY:
239
AN XY:
74424
show subpopulations
Gnomad4 AFR
AF:
0.00123
Gnomad4 AMR
AF:
0.00190
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00123
Gnomad4 NFE
AF:
0.00562
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.00353
Hom.:
1
Bravo
AF:
0.00331
TwinsUK
AF:
0.00566
AC:
21
ALSPAC
AF:
0.00701
AC:
27
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00431
AC:
37
ExAC
AF:
0.00330
AC:
398
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Uncertain:3Benign:19Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:6
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 22, 2016- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsAug 12, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 14, 2020This variant is associated with the following publications: (PMID: 18813041, 23476141, 27147545, 23394784, 22473935, 24195946, 23329375, 25735680, 21918424, 27153395, 26332594, 27058611, 27663056, 28326467, 26019235, 30842289, 32381029) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024RYR1: BS2 -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Malignant hyperthermia, susceptibility to, 1 Benign:5
Benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 01, 2013- -
Benign, reviewed by expert panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenMar 17, 2021This 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 Aspartic Acid with Histidine at codon 4505 of the RYR1 protein, p.(Asp4505His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0054, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1. -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 01, 2022- -
Benign, criteria provided, single submitterclinical testingMendelicsAug 22, 2023- -
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 27, 2024- -
Malignant hyperthermia of anesthesia Benign:2Other:1
Likely benign, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonMar 11, 2015- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 01, 2023Variant summary: RYR1 c.13513G>C (p.Asp4505His) results in a non-conservative amino acid change located in the ryanodine receptor TM 4-6 domain (IPR009460) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 206460 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype determined by the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (0.0054 vs 0.0038; Johnston_2021), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13513G>C has been reported in the literature in individuals affected with malignant hyperthermia susceptibility, King-Denborough syndrome, congenital myopathy, RYR1-related late-onset axial myopathy, core myopathy, idiopathic hyperCKemia and atrioventricular septal defect; however no strong evidences of pathogenicity were found in these studies (e.g. Malandrini_2008, Groom_2011, Klein_2012, Maggi_2013, Loseth_2013, Klingler_2014, Gillies_2015, Priest_2016, Jokela_2019, Elliott_2022, Fusto_2022). Thus, these reports do not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility or other RYR2-related disorders. This variant was found to cause a modest increase in caffeine sensitivity as compared to the wild type protein, and to further enhance such sensitivity when present in cis or trans with another variant, p.R3983C (Groom_2011). Twelve submitters, including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2)/likely benign (n=6) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 07, 2020- -
RYR1-related disorder Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 16, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Congenital hip dislocation;C0699743:Congenital muscular dystrophy;C0746674:Generalized muscle weakness;C4021726:EMG: myopathic abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaNov 14, 2014- -
Myopathy, progressive axial with cataracts Benign:1
Likely benign, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 06, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Pathogenic
0.21
CADD
Benign
22
DANN
Benign
0.46
DEOGEN2
Pathogenic
0.85
.;D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.028
T;T
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.5
.;M
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0050
D;D
Polyphen
1.0
D;D
Vest4
0.77
MVP
0.99
MPC
0.68
ClinPred
0.053
T
GERP RS
3.9
Varity_R
0.57
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0023
dbscSNV1_RF
Benign
0.020
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.

Other links and lift over

dbSNP: rs150396398; hg19: chr19-39057626; COSMIC: COSV99051964; COSMIC: COSV99051964; API