rs1555937233

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000166.6(GJB1):c.548G>A(p.Arg183His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,732 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 10.0

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 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, 0.993

PP5

Variant X-71224255-G-A is Pathogenic according to our data. Variant chrX-71224255-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224255-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.548G>A	p.Arg183His	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.548G>A	p.Arg183His	missense_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	XM_011530907.3 link	c.548G>A	p.Arg183His	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.548G>A	p.Arg183His	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1093732

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360942

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.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 10, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with X-linked Charcot-Marie-Tooth neuropathy, type 1 (CMTX1). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes aberrant cellular localization of this gap junction protein (PMID: 12111842). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Computational tools predict that this variant is damaging. -

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R183H pathogenic mutation (also known as c.548G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 548. The arginine at codon 183 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in several different families of various origin (Bort S et al. Hum Genet, 1997 Jun;99:746-54; Mersiyanova IV et al. Hum Mutat, 2000;15:340-7; Hattori N et al. Brain, 2003 Jan;126:134-51; Chen CX et al. Ann Clin Transl Neurol, 2020 12;7:2381-2392; Kochaski A et al. J Appl Genet, 2004;45:95-100; Niu J et al. Front Neurol, 2019 Jan;10:1406; Chen B et al. Clin Neurol Neurosurg, 2019 Sep;184:105430; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Zhang RX et al. Beijing Da Xue Xue Bao Yi Xue Ban, 2005 Feb;37:68-71; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Micheau P et al. Ann Chir Plast, 1975;20:311-8). Experimental studies show this alteration led to abnormal protein function (Kleopa KA et al. J Neurosci Res, 2002 Jun;68:522-34). (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Charcot-Marie-Tooth Neuropathy X

Pathogenic:1

Aug 31, 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 histidine, which is basic and polar, at codon 183 of the GJB1 protein (p.Arg183His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type X (PMID: 9187667, 14960772, 15719046, 27027447, 27844031, 28469099). ClinVar contains an entry for this variant (Variation ID: 447435). 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 not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12111842, 27844031). This variant disrupts the p.Arg183 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9187667, 11271367, 12111842). 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 X-linked dominant 1

Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

0.63

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.76

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;D

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;.;.;.;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;M

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-4.1

D;.;D;.;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.024

D;.;D;.;D

Sift4G

Uncertain

0.014

D;.;D;.;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.94

MutPred

0.91

Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);Gain of ubiquitination at K187 (P = 0.0624);

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

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