X-71224174-T-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.467T>G(p.Leu156Arg) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
GJB1
NM_000166.6 missense
NM_000166.6 missense
Scores
12
4
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, 0.964
PP5
Variant X-71224174-T-G is Pathogenic according to our data. Variant chrX-71224174-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224174-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.467T>G | p.Leu156Arg | missense_variant | 2/2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.467T>G | p.Leu156Arg | missense_variant | 2/2 | NP_001091111.1 | ||
GJB1 | XM_011530907.3 | c.467T>G | p.Leu156Arg | missense_variant | 2/2 | XP_011529209.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.467T>G | p.Leu156Arg | missense_variant | 2/2 | 1 | NM_000166.6 | ENSP00000354900.6 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 25, 2024 | This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:15006706) The variant is located in a region that is considered important for protein function and/or structure. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2023 | Reported in families with X-linked Charcot-Marie-Tooth disease in published literature (Bergoffen et at., 1993; Bone et al., 1995); Published functional studies demonstrate that L156R mutant formed defective junctional channels (Wang et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15006706, 9361298, 7477983, 26955336, 8266101) - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 12, 2020 | The p.L156R variant (also known as c.467T>G), located in coding exon 1 of the GJB1 gene, results from a T to G substitution at nucleotide position 467. The leucine at codon 156 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). It has been identified in multiple individuals with X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) (Shy ME et al. Neurology, 2007 Mar;68:849-55; Siskind CE et al. J. Peripher. Nerv. Syst., 2011 Jun;16:102-7; Bergoffen J et al. Science, 1993 Dec;262:2039-42; Wu N et al. Case Rep Neurol Dec;7:247-52; Bone LJ et al. Neurology, 1995 Oct;45:1863-6). A functional study shows that this variant leads to reduced production of junctional current and has negative impacts on neurobiotin transfer (Wang HL et al. Neurobiol. Dis., 2004 Mar;15:361-70). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 156 of the GJB1 protein (p.Leu156Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9018031, 17353473, 26955336). ClinVar contains an entry for this variant (Variation ID: 10437). 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 GJB1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 15006706). For these reasons, this variant has been classified as Pathogenic. - |
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1995 | - - |
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
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;M;M
PrimateAI
Uncertain
T
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
Gain of methylation at L156 (P = 0.0032);Gain of methylation at L156 (P = 0.0032);Gain of methylation at L156 (P = 0.0032);Gain of methylation at L156 (P = 0.0032);Gain of methylation at L156 (P = 0.0032);
MVP
MPC
2.0
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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