rs118192179

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000540.3(RYR1):​c.14378T>C​(p.Leu4793Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

RYR1
NM_000540.3 missense

Scores

13
3
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 7.98
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a transmembrane_region Helical; Name=3 (size 22) in uniprot entity RYR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000540.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 19-38579995-T-C is Pathogenic according to our data. Variant chr19-38579995-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65962.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Pathogenic=1}. Variant chr19-38579995-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR1NM_000540.3 linkuse as main transcriptc.14378T>C p.Leu4793Pro missense_variant 100/106 ENST00000359596.8 NP_000531.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkuse as main transcriptc.14378T>C p.Leu4793Pro missense_variant 100/1065 NM_000540.3 ENSP00000352608 A2P21817-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Other:1
not provided, no classification providedliterature onlyLeiden Muscular Dystrophy (RYR1)-- -
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 24, 2016- -
Central core myopathy Pathogenic:1
Pathogenic, no assertion criteria providedcurationGeneReviewsMay 11, 2010- -
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 02, 2021For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with autosomal dominant central core disease (PMID: 11709545, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65962). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 4793 of the RYR1 protein (p.Leu4793Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
25
DANN
Benign
0.94
DEOGEN2
Pathogenic
0.83
.;D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
.;M
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.6
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.023
D;D
Polyphen
1.0
D;D
Vest4
0.95
MutPred
0.88
.;Loss of catalytic residue at L4793 (P = 0.0019);
MVP
0.99
MPC
1.4
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.91
gMVP
0.99

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: rs118192179; hg19: chr19-39070635; API