rs116840818

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000166.6(GJB1):c.187G>A(p.Val63Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,096,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7U:2O:1

Conservation

PhyloP100: 10.0

Variant links:

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]

GJB1 links:

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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, 0.985

PP5

Variant X-71223894-G-A is Pathogenic according to our data. Variant chrX-71223894-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71223894-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.187G>A	p.Val63Ile	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.187G>A	p.Val63Ile	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.187G>A	p.Val63Ile	missense_variant	Exon 2 of 2		XP_011529209.1	P08034A0A654ICJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.187G>A	p.Val63Ile	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096578

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

361988

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Mar 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with CMTX1 (PMID: 8162049, 25025039) and is associated with a mild to moderate clinical presentation in both males and females (PMID: 9364054); Functional studies in murine cells demonstrate that at least some of the V63I variant protein is able to localize to the cell surface, shows no significant effect on the ability of the mutant protein to form gap junctions, and to date have failed to elucidate the pathogenic mechanism of the V63I mutant protein (PMID: 9364054, 15006706); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10093067, 30569560, 15006706, 20301548, 9099841, 12477701, 9633821, 12542510, 11393532, 17100997, 25025039, 9361298, 32376792, 37284795, 8162049, 9364054) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 30, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease X-linked dominant 1

Uncertain:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 63 of the GJB1 protein (p.Val63Ile). 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: 8162049, 10093067, 12542510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21081). 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 GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 11393532, 15006706). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

D;D;D;D;D;.;D

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

.;.;.;.;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M;M;.;.;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.99

N;.;N;.;N;.;N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0090

D;.;D;.;D;.;D

Sift4G

Uncertain

0.020

D;.;D;.;D;.;D

Polyphen

1.0

D;D;D;D;.;.;D

Vest4

0.78

MutPred

0.96

Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);Loss of catalytic residue at V63 (P = 0.2318);

MVP

0.95

MPC

1.7

ClinPred

0.98

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over