rs1555937122
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.266T>C(p.Leu89Pro) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
GJB1
NM_000166.6 missense
NM_000166.6 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-71223973-T-C is Pathogenic according to our data. Variant chrX-71223973-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 447428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223973-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | NP_001091111.1 | ||
GJB1 | XM_011530907.3 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | XP_011529209.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | 1 | NM_000166.6 | ENSP00000354900 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2017 | This sequence change replaces leucine with proline at codon 89 of the GJB1 protein (p.Leu89Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have found that this missense change impacts the cellular localization of the GJB1-encoded CX32 protein, preventing the formation of functional CX32 gap junctions (PMID: 27367520). This variant has been reported in multiple individuals affected with CMTX1 (PMID: 26274329, 12457340, 9099841) and it has been reported to segregate with disease in a family affected with X-linked dominant Charcot-Marie-Tooth disease (CMTX1) (PMID: 17714866). This variant is also known as leu238pro in the literature. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 13, 2016 | - - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;.;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;.;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;.;D
Sift4G
Pathogenic
D;.;D;.;.;D
Polyphen
D;D;D;D;.;D
Vest4
MutPred
Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);
MVP
MPC
2.3
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