19-38496294-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PS4_ModeratePP3_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 phenylalanine at codon 2210 of the RYR1 protein, p.Val2210Phe. 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, two 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_Supporting (PMID:15731587, The UK (Leeds) MH Unit, Prevention Genetics). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). A REVEL score >0.85 (0.961) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA024625/MONDO:0007783/012

Frequency

Genomes: not found (cov: 32)

Consequence

RYR1
NM_000540.3 missense

Scores

14
3
1

Clinical Significance

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

Conservation

PhyloP100: 10.0
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 6 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
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/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.6628G>T p.Val2210Phe missense_variant 40/106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.6628G>T p.Val2210Phe missense_variant 40/1065 NM_000540.3 ENSP00000352608.2 P21817-1
RYR1ENST00000355481.8 linkuse as main transcriptc.6628G>T p.Val2210Phe missense_variant 40/1051 ENSP00000347667.3 P21817-2
RYR1ENST00000594335.5 linkuse as main transcriptn.79G>T non_coding_transcript_exon_variant 1/491 ENSP00000470927.2 M0R014
RYR1ENST00000599547.6 linkuse as main transcriptn.6628G>T non_coding_transcript_exon_variant 40/802 ENSP00000471601.2 M0R127

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 18, 2024The c.6628G>T (p.Val2210Phe) variant, located on the exon 40 of the RYR1 gene, replaces valine with phenylalanine at codon 2210 of the RYR1 protein. This missense variant has been observed in at least three unrelated individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 15731587, 1836259, 35849058). This variant is in a mutational hotspot that has been reported to contribute to malignant hyperthermia susceptibility (MHS) (PMID: 21118704). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. This variant has been classified as likely pathogenic by the expert review panel in CliVar (ID: 133165). This variant is absent in the general population database by gnomAD. For these reasons, the c.6628G>T (p.Val2210Phe) variant of RYR1 is classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panelcurationClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGenApr 06, 2023This 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 phenylalanine at codon 2210 of the RYR1 protein, p.Val2210Phe. 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, two 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_Supporting (PMID:15731587, The UK (Leeds) MH Unit, Prevention Genetics). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score >0.85 (0.961) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate. -
not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 10, 2020- -
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
RYR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2022ClinVar contains an entry for this variant (Variation ID: 133165). This missense change has been observed in individuals with malignant hyperthermia (PMID: 15731587; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2210 of the RYR1 protein (p.Val2210Phe). 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 expected to disrupt RYR1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
.;D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.89
MutPred
0.90
Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);
MVP
0.99
MPC
0.50
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.80
gMVP
0.94

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.

Other links and lift over

dbSNP: rs193922792; hg19: chr19-38986934; API