rs756928158

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000166.6(GJB1):c.271G>A(p.Val91Met) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V91G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 10.0

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 1
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000166.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-71223979-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2664352.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant X-71223978-G-A is Pathogenic according to our data. Variant chrX-71223978-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GJB1	NM_000166.6 link	c.271G>A	p.Val91Met	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3 link	c.271G>A	p.Val91Met	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1 link	c.271G>A	p.Val91Met	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.271G>A	p.Val91Met	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

165556

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GJB1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3

Mar 02, 2015

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:2

Jun 10, 2022

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PS3,PM1,PM2,PP3,PP5

Dec 13, 2019

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GJB1 c.271G>A (p.Val91Met) variant is a missense variant that has been reported in a heterozygous state in at least eight individuals with Charcot-Marie-Tooth neuropathy (Bissar-Tadmouri et al. 2000; Dobourg et al. 2001; Michelle et al. 2009; Arthur-Farraj et al. 2012; Tsai et al. 2016; Hong et al. 2017). Affected individuals presented with motor neuropathy, areflexia, ataxia, paresthesia of the feet, numbness and/or weakness of lower limbs, and sensorineural hearing loss in at least one affected individual. Age of onset was variable, but generally occurred in the first or second decade. The p.Val91Met variant was absent from 50 control individuals (Dobourg et al. 2001) and is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Functional studies in HeLa cells showed decreased expression of the p.Val91Met variant protein in the plasma membrane compared to controls (Tsai et al. 2016). In addition, the variant protein was mainly localized to the cytoplasm and showed fewer gap junction plaques at the intercellular boundaries compared to wild-type. Additional tests were conducted in HEK293T cells where Ca2+ signaling propagation was evaluated. Impaired gap junction permeability was observed and the onset-to-peak duration of the signal was longer in cells expressing the p.Val91Met variant compared to those expressing wild-type protein (Tsai et al. 2016). The p.Val91Met variant is located in the second transmembrane domain which is suggested to be important for protein conformation. Based on the collective evidence, the p.Val91Met variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1.

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Jan 11, 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 91 of the GJB1 protein (p.Val91Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMTX (PMID: 11140841, 11571214, 22464564, 27027447, 27844031, 28097225). ClinVar contains an entry for this variant (Variation ID: 195025). 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) indicates that this missense variant is expected to disrupt GJB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;.;D

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.0

.;.;.;.;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;H;H;.;H

PhyloP100

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;.;D;.;.;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;.;D;.;.;D

Sift4G

Uncertain

0.0040

D;.;D;.;.;D

Vest4

0.76

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over