rs768834663

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000166.6(GJB1):c.83T>A(p.Ile28Asn) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 22)

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 7.99

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 Likely_pathogenic. Variant got 9 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, 0.987

PP5

Variant X-71223790-T-A is Pathogenic according to our data. Variant chrX-71223790-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215983.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}. Variant chrX-71223790-T-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.83T>A	p.Ile28Asn	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.83T>A	p.Ile28Asn	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.83T>A	p.Ile28Asn	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.83T>A	p.Ile28Asn	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183311

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67757

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 28 of the GJB1 protein (p.Ile28Asn). This variant is present in population databases (rs768834663, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1X (PMID: 9361298; Invitae). ClinVar contains an entry for this variant (Variation ID: 215983). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. This missense change is located in a region of the GJB1 protein in which a significant number of missense variants have been reported (PMID: 21309765). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease X-linked dominant 1

Pathogenic:1

Feb 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB1 p.Ile28Asn variant (rs768834663) was reported in a cohort of patients with CMT from Athena diagnostics (Bone, 1997). Among the 130 variants reported in this cohort, several affecting the same codon (c.83T>C; p.Ile28T) or nearby residues (p.Ser26Leu, p.Val27Ala and p.Ile30Asn) were observed in affected patients. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0005 percent (identified on 1 out of 183,311 chromosomes), and reported to ClinVar as a pathogenic variant (Variation ID: 215983). The isoleucine at position 28 is highly conserved across the vertebrates and located in a transmembrane domain. Computational analyses of the p.Ile28Asn variant on protein structure and function indicates a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on these observations, the p.Ile28Asn variant is likely to be pathogenic. References: Bone et al. Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 1997;4(3-4):221-30. -

Inborn genetic diseases

Uncertain:1

Mar 26, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I28N variant (also known as c.83T>A), located in coding exon 1 of the GJB1 gene, results from a T to A substitution at nucleotide position 83. The isoleucine at codon 28 is replaced by asparagine, an amino acid with dissimilar properties. This alteration was detected in a cohort of patients with Charcot–Marie–Tooth disease (Bone LJ et al. Neurobiol. Dis., 1997;4:221-30). Based on data from gnomAD, the A allele has an overall frequency of 0.0005% (1/183,311) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.001% (1/81,818) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

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

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;L;L;L;.;.;L

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.7

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.99

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

Vest4

0.93

MutPred

0.94

Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);Loss of stability (P = 0.0369);

MVP

0.98

MPC

2.3

ClinPred

0.96

GERP RS

4.4

Varity_R

0.92

gMVP

1.0

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