rs104894812

Variant names:

Variant summary

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

The NM_000166.6(GJB1):c.415G>A(p.Val139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

Conservation

PhyloP100: 2.65

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:

Genome browser will be placed here

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, 0.97

PP5

Variant X-71224122-G-A is Pathogenic according to our data. Variant chrX-71224122-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224122-G-A is described in Lovd as [Pathogenic]. Variant chrX-71224122-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.415G>A	p.Val139Met	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.415G>A	p.Val139Met	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.415G>A	p.Val139Met	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.415G>A	p.Val139Met	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000584

AC:

AN:

171137

Hom.:

AF XY:

0.00

AC XY:

AN XY:

57039

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1092662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358430

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:4Other:1

Sep 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2021

Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

3. The p.Val139Met variant in GJB1 has been reported in several families worldwide with Charcot-Marie-Tooth Neuropathy X linked. ClinVar classifies this variant as Pathogenic (Variation ID:10433), 1 star (criteria provided, 4 submissions), citing 7 articles (12402337, 11325342, 9364054, 9272161, 8816997 and 2 more). This variant is in a hotspot region and an important functional domain of the protein (M3). Besides that, this variant segregates with family phenotype. In summary, the p.Val139Met meets our criteria to be classified as pathogenic. -

not provided

Pathogenic:3

Feb 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant exhibits no GJIC capacity function, it demonstrates dominant negative down-regulation of GJIC function when co-expressed with wild type, and it alters the formation and structure of gap junction plaques (PMID: 8816997, 28071741); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23279425, 11325342, 9364054, 18714809, 7477983, 10093067, 9099841, 10586284, 11438991, 12477701, 8266101, 28071741, 8800924, 10586261, 12402337, 9820654, 34326750, 32376792, 30340945, 8816997, 9272161) -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB1: PP1:Strong, PM2, PM5, PS4:Moderate -

Mar 14, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM5, PS3, PS4 -

Inborn genetic diseases

Pathogenic:1

Jan 15, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V139M pathogenic mutation (also known as c.415G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 415. The valine at codon 139 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), and it has been found to segregate with CMTX1 in multiple families (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35; Halbrich M et al. Can J Neurol Sci, 2008 Jul;35:372-4; Hoebeke C et al. Arch Pediatr, 2018 Nov;25:452-458; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Silander K et al. Hum Genet, 1997 Sep;100:391-7). Functional studies indicate that this alteration impairs gap junction formation and results in altered pattern of trafficking and localization (Omori Y et al. Mol Biol Cell, 1996 Jun;7:907-16; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Abrams CK et al. Brain Res, 2001 May;900:9-25; Abrams CK et al. Sci Rep, 2017 01;7:40166). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Jan 23, 2025

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 methionine, which is neutral and non-polar, at codon 139 of the GJB1 protein (p.Val139Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9272161, 9364054). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10433). Invitae Evidence 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 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: 8816997, 11325342). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;D;D;D;D

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

.;.;.;.;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;M;M;M;M

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.010

N;.;N;.;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

D;.;D;.;D

Sift4G

Uncertain

0.0040

D;.;D;.;D

Polyphen

0.99

D;D;D;D;D

Vest4

0.58

MutPred

0.86

Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);Gain of MoRF binding (P = 0.0988);

MVP

0.98

MPC

1.6

ClinPred

0.69

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.95

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