rs118192138
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.13949T>C(p.Leu4650Pro) variant causes a missense change. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L4650L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
RYR1
NM_000540.3 missense
NM_000540.3 missense
Scores
9
4
3
Clinical Significance
Conservation
PhyloP100: 5.08
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 17 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000540.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RYR1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 19-38572221-T-C is Pathogenic according to our data. Variant chr19-38572221-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38572221-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.13949T>C | p.Leu4650Pro | missense_variant | 95/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.13949T>C | p.Leu4650Pro | missense_variant | 95/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 06, 2018 | The p.Leu4650Pro variant has been previously reported in an affected child who also carried p.Lys4724Gln variant on the other allele (Romero 2003). She was born at 37 weeks of gestation with prenatal history of hydramnion, fetal akinesia and breach presentation. She presented with multiple arthrogryposis, severe hypotonia, amyotrophy and hypomimia, and required respiratory mechanical assistance. Muscle biopsy at two months of age showed type I fiber predominance, unique large eccentric cores, some necrotic or regenerative fibers and connective tissue increase. At age 5, she was reported to have delayed motor development, ptosis and strabismus (Romero 2003). The p.Leu4650Pro variant is listed in ClinVar (Variation ID 65961). Additionally, in vitro functional studies with p.Phe1528Leu demonstrated that this variant results in excitation-contraction uncoupling by reducing channel opening in the absence of a change in calcium ion permeation (Dulhunty et al.) - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
Central core myopathy Pathogenic:1
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 11, 2010 | - - |
RYR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 03, 2023 | 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. Experimental studies have shown that this missense change affects RYR1 function (http://aups.org.au/Proceedings/43/186P/). 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. ClinVar contains an entry for this variant (Variation ID: 65961). This missense change has been observed in individuals with clinical features of autosomal recessive congenital myopathy (PMID: 12937085; externalcommunication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4650 of the RYR1 protein (p.Leu4650Pro). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
0.93
.;Loss of helix (P = 0.0072);
MVP
MPC
1.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at