rs104894821

Variant names:

• chrX-71223990-G-A
• rs104894821
• NM_000166.6:c.283G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.283G>A​(p.Val95Met) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 8.15
• Publications: 20 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 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, 0.99
• PP5: Variant X-71223990-G-A is Pathogenic according to our data. Variant chrX-71223990-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.283G>A	p.Val95Met	missense	Exon 2 of 2	NP_000157.1
	GJB1	NM_001097642.3		c.283G>A	p.Val95Met	missense	Exon 2 of 2	NP_001091111.1
	GJB1	NM_001440770.1		c.283G>A	p.Val95Met	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.283G>A	p.Val95Met	missense	Exon 2 of 2	ENSP00000354900.6
	GJB1	ENST00000374029.2	TSL:5	c.283G>A	p.Val95Met	missense	Exon 2 of 2	ENSP00000363141.1
	GJB1	ENST00000447581.2	TSL:5	c.283G>A	p.Val95Met	missense	Exon 3 of 3	ENSP00000407223.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000802 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Sep 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB1 c.283G>A; p.Val95Met variant (rs104894821) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (Bone 1995, Kim 2017, Nam 2016, Montenegro 2011). This variant is reported in ClinVar (Variation ID: 10441), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 95 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a significant defect in channel formation and function (Ressot 1998, Wang 2004). Based on available information, this variant is considered to be pathogenic. References: Bone LJ et al. New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. Neurology. 1995 Oct;45(10):1863-6. Kim JK et al. X-linked Charcot-Marie-Tooth disease with GJB1 mutation presenting as acute disseminated encephalomyelitis-like illness: A case report. Medicine (Baltimore). 2017 Dec;96(49):e9176. Montenegro G et al. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol. 2011 Mar;69(3):464-70. Nam SH et al. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. Mol Cells. 2016 May 31;39(5):382-8. 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. Wang HL et al. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004 Mar;15(2):361-70.

Dec 06, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PP3

Oct 22, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:3

Mar 24, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate V95M prevents formation of functional channels (Ressot et al., 1998; Wang et al., 2004); 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: 23649551, 27098783, 23293578, 9361298, 9401007, 10873293, 15006706, 7477983, 29245364, 27025386, 16922730, 17353473, 10751669, 12067629, 10093067, 10586261, 9592087, 21254193, 31827005, 32399692, 32376792)

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 27, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Sep 06, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V95M variant (also known as c.283G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 283. The valine at codon 95 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Volodarsky M et al. J Med Genet, 2021 04;58:284-288; Bone LJ et al. Neurology, 1995 Oct;45:1863-6; Hahn AF et al. Ann N Y Acad Sci, 1999 Sep;883:366-82; Dubourg O et al. Brain, 2001 Oct;124:1958-67; Liu X et al. Front Neurol, 2020 Jul;11:690; Kim JK et al. Medicine (Baltimore), 2017 Dec;96:e9176; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Sun B et al. J Peripher Nerv Syst, 2017 03;22:13-18; Shahrizaila N et al. Muscle Nerve, 2014 Feb;49:198-201; Montenegro G et al. Ann Neurol, 2011 Mar;69:464-70; Park HK et al. Clin Genet, 2006 Sep;70:253-6; Rouger H et al. Hum Mutat, 1997;10:443-52). Multiple functional assays show that V95M has reduced junctional conductance and diffusion of small molecules between cells in vitro (Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70; Ressot C et al. J Neurosci, 1998 Jun;18:4063-75). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 95 of the GJB1 protein (p.Val95Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked Charcot-Marie-Tooth (CMT) disease (PMID: 10586261, 10873293, 16922730, 21254193). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10441). 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 expected to disrupt GJB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9592087, 21254193). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.95		Gain of disorder (P = 0.0665)
MVP		1.0
MPC		1.9
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.93
gMVP		0.98
Mutation Taster		=5/95	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

Other links and lift over

dbSNP: rs104894821; hg19: chrX-70443840;