rs1241595912

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000166.6(GJB1):c.491G>A(p.Arg164Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,603 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 10.0

Publications

28 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 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-71224197-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.912

PP5

Variant X-71224198-G-A is Pathogenic according to our data. Variant chrX-71224198-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 543920.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.491G>A	p.Arg164Gln	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3 link	c.491G>A	p.Arg164Gln	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1 link	c.491G>A	p.Arg164Gln	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.491G>A	p.Arg164Gln	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000580

AC:

AN:

172347

AF XY:

0.00

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 FIN exome

AF:

0.0000716

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000183

AC:

AN:

1093603

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359613

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26339

American (AMR)

AF:

0.00

AC:

AN:

34778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19275

East Asian (EAS)

AF:

0.00

AC:

AN:

30109

South Asian (SAS)

AF:

0.00

AC:

AN:

53464

European-Finnish (FIN)

AF:

0.0000256

AC:

AN:

39040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840534

Other (OTH)

AF:

0.00

AC:

AN:

45932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GJB1: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, including reduced plasma membrane expression of GJB1 and GJ plaque formation combined with predominant cytoplasmic retention of GJB1, and impaired GJ permeability (Tsai et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10220155, 10737979, 12497641, 11571214, 23649551, 7580242, 9187667, 27098783, 18379723, 26454100, 9854984, 10923043, 17100997, 25025039, 20443038, 27544631, 15241803, 9361298, 14663027, 27844031, 15006706, 27025386, 27027447, 22243284, 31211173, 32022442, 31948496, 33726816) -

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:2

Nov 03, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 11, 2024

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.491G>A (p.Arg164Gln) results in a conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-06 in 172347 control chromosomes (gnomAD). c.491G>A has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (e.g. Hsu_2019, Record_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37284795, 31211173). ClinVar contains an entry for this variant (Variation ID: 543920). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Aug 18, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R164Q variant (also known as c.491G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 491. The arginine at codon 164 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu V et al. Neuromuscul Disord, 1995 Jul;5:297-9; Bort S et al. Hum Genet, 1997 Jun;99:746-54; Høyer H et al. Biomed Res Int, 2014 Jun;2014:210401; Michaelidou K et al. Mol Genet Genomic Med, 2020 04;8:e1141; Li LX et al. Oncotarget, 2016 May;7:27655-64; Wang R et al. Clin Chim Acta, 2015 Dec;451:263-70; Braathen GJ. Acta Neurol Scand Suppl, 2012;:iv-22; Yoshihara T et al. Hum Mutat, 2000 Aug;16:177-8; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Choi BO et al. Hum Mutat, 2004 Aug;24:185-6; Dubourg O et al. Brain, 2001 Oct;124:1958-67; Huehne K et al. Hum Mutat, 2003 Jan;21:100; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Experimental studies have shown that this alteration causes mislocalization via cytoplasmic retention of GJB1 and significantly impairs Ca2+ signaling (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This amino acid position is highly 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. -

Peripheral neuropathy

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 164 of the GJB1 protein (p.Arg164Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (PMID: 9187667, 10923043, 11571214, 12497641, 15241803, 22243284, 23106488, 25025039, 26454100, 27027447). ClinVar contains an entry for this variant (Variation ID: 543920). 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: 27844031). This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7580242, 9187667, 15006706, 27025386, 27027447). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Benign

0.34

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D;D;D;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;.;.;.;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.8

M;M;M;M;M

PhyloP100

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.8

D;.;D;.;D

REVEL

Pathogenic

0.85

Sift

Benign

0.077

T;.;T;.;T

Sift4G

Benign

0.25

T;.;T;.;T

Polyphen

1.0

D;D;D;D;D

Vest4

0.72

MutPred

0.64

Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);Loss of methylation at R164 (P = 0.0648);

MVP

1.0

MPC

2.0

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.98

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over