rs104894810

Variant names:

• chrX-71224131-C-T
• rs104894810
• NM_000166.6:c.424C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.424C>T​(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,375 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.138

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]

ACMG classification

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

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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-71224132-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188174.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. 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, 0.992
• PP5: Variant X-71224131-C-T is Pathogenic according to our data. Variant chrX-71224131-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71224131-C-T is described in Lovd as [Pathogenic]. Variant chrX-71224131-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.424C>T	p.Arg142Trp	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.424C>T	p.Arg142Trp	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	XM_011530907.3	c.424C>T	p.Arg142Trp	missense_variant	Exon 2 of 2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.424C>T	p.Arg142Trp	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000588 AC: 1 AN: 170000 AF XY: 0.0000178

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: 0.0000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092375 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 1 AN XY: 358273

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26317

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 34532

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19261

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30030

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 53164

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40173

Gnomad4 NFE exome AF: 0.00000119 AC: 1 AN: 838851

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45916

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000419 Hom.: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:4

Aug 01, 2024

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.424C>T, variant found is located in exon 2. Most predictors characterize the variant as Deleterious (PP3), the patient's phenotype and family history are highly specific for this Mendelian disease: Asymmetric bilateral pes cavus, gait disturbances, suspected hereditary neuropathy (PP4), the variant is located in a well-established functional domain: it is in a Connexin domain, right in the transmembrane passage region (PM1), a rare variant is observed in unrelated individuals with the same phenotype and is absent in control individuals, there are 4 reports in ClinVar of patients with this syndrome and this same variant (VCV000010431.15) (PS4), the variant was not found in the general population (PM2_Supporting), it is a missense variant in a gene with a low benign missense rate (Z score 3.96) (PP2), there are functional studies that show that this variant causes the pathology (PMID:19369543)(PS3) -

Dec 24, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB1: PS4, PM2, PM5, PS3:Moderate, PP3 -

Jan 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, with the R142W variant forming no functional intercellular channels and demonstrating impaired connexon assembly (Bruzzone et al., 1994; VanSlyke et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); 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: 8004109, 22771394, 10207904, 10848620, 9364054, 8266101, 7946361, 28286897) -

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jun 12, 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 tryptophan, which is neutral and slightly polar, at codon 142 of the GJB1 protein (p.Arg142Trp). 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 individual(s) with Charcot-Marie-Tooth disease, type IX (PMID: 8004109, 8266101, 10873293, 25947624). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10431). 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 expected to disrupt GJB1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620). This variant disrupts the p.Arg142 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11571214). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;D
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D;.;D;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.75
MutPred		0.94		Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);Loss of methylation at R142 (P = 0.0386);
MVP		1.0
MPC		1.9
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.93
gMVP		1.0
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894810; hg19: chrX-70443981;