15-51341743-T-C
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_181789.4(GLDN):āc.59T>Cā(p.Leu20Pro) 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 (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GLDN
NM_181789.4 missense
NM_181789.4 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 3.83
Genes affected
GLDN (HGNC:29514): (gliomedin) This gene encodes a protein that contains olfactomedin-like and collagen-like domains. The encoded protein, which exists in both transmembrane and secreted forms, promotes formation of the nodes of Ranvier in the peripheral nervous system. Mutations in this gene cause a form of lethal congenital contracture syndrome in human patients. Autoantibodies to the encoded protein have been identified in sera form patients with multifocal motor neuropathy. [provided by RefSeq, May 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.778
PP5
Variant 15-51341743-T-C is Pathogenic according to our data. Variant chr15-51341743-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813924.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-51341743-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLDN | NM_181789.4 | c.59T>C | p.Leu20Pro | missense_variant | 1/10 | ENST00000335449.11 | NP_861454.2 | |
GLDN | XM_017022121.2 | c.59T>C | p.Leu20Pro | missense_variant | 1/9 | XP_016877610.1 | ||
GLDN | XM_017022125.1 | c.59T>C | p.Leu20Pro | missense_variant | 1/10 | XP_016877614.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLDN | ENST00000335449.11 | c.59T>C | p.Leu20Pro | missense_variant | 1/10 | 2 | NM_181789.4 | ENSP00000335196.6 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1311044Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 645912
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
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1311044
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Cov.:
30
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0
AN XY:
645912
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lethal congenital contracture syndrome 11 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Leu20Pro variant in GLDN was identified by our study in the compound heterozygous state, with a VUS, in three siblings with lethal congenital contracture syndrome. This variant segregated with disease in all three siblings, and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies conducted by our collaborators provide some evidence that the p.Leu20Pro variant may impact protein function by preventing localization to the cell membrane in cell-based assays, similarly to other variants identified in individuals with Lethal Arthrogyposis (PMID: 27616481). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP1 (Richards 2015). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of loop (P = 0.002);
MVP
MPC
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