rs779696968

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000166.6(GJB1):c.305A>G(p.Glu102Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,228 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E102D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.34

Publications

17 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 17 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000166.6

PM2

Very rare variant in population databases, with high coverage;

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, 0.972

PP5

Variant X-71224012-A-G is Pathogenic according to our data. Variant chrX-71224012-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 216038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.305A>G	p.Glu102Gly	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.305A>G	p.Glu102Gly	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.305A>G	p.Glu102Gly	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.305A>G	p.Glu102Gly	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

AF:

0.00000899

AC:

AN:

111228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

169210

AF XY:

0.0000181

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000899

AC:

AN:

111228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30596

American (AMR)

AF:

0.00

AC:

AN:

10461

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3497

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52948

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 05, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (homotypic channels differ from wild type in sensitivity and time course; impairs modulatory function of Schwann cells on axons, resulting in profound cytoskeletal alterations leading to distal axonal degeneration) (Ressot et al., 1998; Sahenk et al., 1998); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9354338, 22771394, 25614874, 8004109, 9592087, 8737658, 17353473, 14627639, 9469571, 31827005, 11835375, 10873293) -

May 18, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant has frequently been reported to result in a milder phenotype in patients when compared to complete loss-of-function variants (PMID: 8737658, 14627639, 27228968). In some published literature, this variant is referred to as 367A>G. Assessment of experimental evidence suggests this variant results in abnormal protein function. In functional studies, this variant formed channels, but these displayed abnormal voltage gating and dysfunction during acidification (consistent with the milder phenotype reported), as well as lower myelinated fiber density (PMID: 9592087, 14627639). -

Sep 17, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4 -

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:2

Mar 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GJB1 c.305A>G; p.Glu102Gly variant (rs779696968) is described in the literature in individuals and families with Charcot-Marie-Tooth (CMT) and is reported as a frequently detected variant in individuals with CMT (Cortese 2020, DiVincenzo 2014, Ionasescu 1994). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 216038) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved computational analyses predict that this variant is deleterious (REVEL: 0.877). In support of this prediction, functional studies show this variant alters the voltage-gating, resulting in increased sensitivity to intracellular acidification (Abrams 2003, Ressot 1998). Based on available information, this variant is classified as pathogenic. References: Abrams CK et al Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J Neurosci. 2003 Nov 19;23(33):10548-58. PMID: 14627639. Cortese A et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology. 2020 Jan 7;94(1):e51-e61. PMID: 31827005. DiVincenzo C et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9. PMID: 25614874. Ionasescu V et al. Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Hum Mol Genet. 1994 Feb;3(2):355-8. 8004109. Ressot C et al. Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci. 1998 Jun 1;18(11):4063-75. PMID: 9592087 -

Apr 14, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GJB1 c.305A>G (p.Glu102Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 169210 control chromosomes (gnomAD). c.305A>G has been observed in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (Ionasescu_1998, Record_2023). These data indicate that the variant is very likely to be associated with disease. Two publications reported experimental evidence evaluating an impact on protein function and this variant affected the GJB1 protein function (Oh_1997, Ressot_1998). The following publications have been ascertained in the context of this evaluation (PMID: 10873293, 9354338, 37284795, 9592087). ClinVar contains an entry for this variant (Variation ID: 216038). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jan 04, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E102G variant (also known as c.305A>G), located in coding exon 1 of the GJB1 gene, results from an A to G substitution at nucleotide position 305. The glutamic acid at codon 102 is replaced by glycine, an amino acid with similar properties. This variant has been reported in multiple unrelated individuals affected with X-linked Charcot-Marie-Tooth disease (CMT) and was confirmed de novo in one individual as well as shown to segregate with the disease in another family (Ionasescu V et al. Hum. Mol. Genet., 1994 Feb;3:355-8; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84; Boerkoel CF et al. Ann. Neurol., 2002 Feb;51:190-201; Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58; Siskind CE et al. J Peripher Nerv Syst, 2011 Jun;16:102-7; Record CJ et al. Brain, 2023 Oct;146:4336-4349). Experimental studies have shown that nerve xenografts from the patients with E102G showed altered Schwann cell membrane composition/organization, leading to axonal abnormalities (Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84). Moreover, studies using Xenopus oocytes showed that this variant increased sensitivity of channels to intracellular acidification, affecting junctional conductance (Oh S et al. Neuron, 1997 Oct;19:927-38; Sahenk Z et al. J. Neurosci. Res., 1998 Jan;51:174-84; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Abrams CK et al. J. Neurosci., 2003 Nov;23:10548-58). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 102 of the GJB1 protein (p.Glu102Gly). 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 X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8004109, 14627639, 17353473, 25614874). ClinVar contains an entry for this variant (Variation ID: 216038). 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: 9354338, 9469571, 9592087, 14627639). 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

0.57

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

.;.;.;.;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;M

PhyloP100

7.3

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.9

D;.;D;.;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;.;D;.;D

Sift4G

Uncertain

0.0030

D;.;D;.;D

Polyphen

0.96

D;D;D;D;D

Vest4

0.80

MutPred

0.84

Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);Loss of stability (P = 0.0314);

MVP

1.0

MPC

1.6

ClinPred

0.77

GERP RS

4.7

Varity_R

0.71

gMVP

0.98

Mutation Taster

=36/64

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

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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