19-38565034-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_ModeratePP3_ModeratePP1PS1_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 valine with leucine at codon 4234 of the RYR1 protein, p.(Val4234Leu); c.12700G>T. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight 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_Moderate (PMID:24013571, The UK (Leeds) MH Unit). This variant segregates with MHS in two families, four meioses, PP1_Supporting (PMID:24013571). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Another variant at this same nucleotide position, resulting in the same amino acid variation has been classified as pathogenic, PS1_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS1_Moderate, PS4_Moderate, PP1_Supporting, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA405670953/MONDO:0018493/012

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RYR1
NM_000540.3 missense

Scores

10
5
3

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 8.00
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 Likely_pathogenic. Variant got 7 ACMG points.

PS1
For more information check the summary or visit ClinGen Evidence Repository.
PS4
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
RYR1NM_000540.3 linkc.12700G>T p.Val4234Leu missense_variant Exon 91 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.12700G>T p.Val4234Leu missense_variant Exon 91 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1430864
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
708744
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

RYR1-related disorder Pathogenic:1
Feb 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4234 of the RYR1 protein (p.Val4234Leu). 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 susceptibility (PMID: 12208234, 21965348, 24013571, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1071064). 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. For these reasons, this variant has been classified as Pathogenic. -

Malignant hyperthermia of anesthesia Pathogenic:1
Apr 07, 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 valine with leucine at codon 4234 of the RYR1 protein, p.(Val4234Leu); c.12700G>T. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight 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_Moderate (PMID: 24013571, The UK (Leeds) MH Unit). This variant segregates with MHS in two families, four meioses, PP1_Supporting (PMID: 24013571). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Another variant at this same nucleotide position, resulting in the same amino acid variation has been classified as pathogenic, PS1_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS1_Moderate, PS4_Moderate, PP1_Supporting, PP3_Moderate. -

not provided Pathogenic:1
Mar 27, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24013571, 19191333, 30236257) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
23
DANN
Benign
0.97
DEOGEN2
Uncertain
0.73
.;D
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.5
.;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-2.3
N;N
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0030
D;D
Polyphen
0.71
P;P
Vest4
0.61
MutPred
0.84
.;Loss of ubiquitination at K4229 (P = 0.1852);
MVP
0.99
MPC
0.56
ClinPred
0.97
D
GERP RS
3.1
Varity_R
0.45
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39055674; API