VCV000406232.7 - ClinVar

NM_000166.6(GJB1):c.178T>C (p.Cys60Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (1)

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000166.6(GJB1):c.178T>C (p.Cys60Arg)

Variation ID: 406232 Accession: VCV000406232.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 70443735 (GRCh37) [ NCBI UCSC ] X: 71223885 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 2, 2017	Feb 15, 2026	Nov 26, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000166.6:c.178T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000157.1:p.Cys60Arg	missense
NM_001097642.3:c.178T>C	NP_001091111.1:p.Cys60Arg	missense
NC_000023.11:g.71223885T>C
NC_000023.10:g.70443735T>C
NG_008357.1:g.13674T>C
LRG_245:g.13674T>C
LRG_245t2:c.178T>C	LRG_245p2:p.Cys60Arg

... more HGVS ... less HGVS

Protein change

C60R

Other names

Canonical SPDI

NC_000023.11:71223884:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA16616545 dbSNP: rs1060501004 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GJB1		-	-	GRCh38 GRCh37	870	1003

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth Neuropathy X	Pathogenic (1)	criteria provided, single submitter	Nov 26, 2025	RCV000456635.8
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 8, 2017	RCV000493246.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 08, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000582068.4 First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017	Comment: show A variant that is likely pathogenic has been identified in the GJB1 gene. The C60R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid substitution at the same position (C60F) has been previously reported in a family with CMTX1 (Fairweather et al., 1994). The C60R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C60R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Charcot-Marie-Tooth Neuropathy X	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000544781.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 10093067‚ 25043634‚ 28492532‚ 8162049‚ 8816997‚ 9452099 Comment: show This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 60 of the GJB1 protein (p.Cys60Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (internal data). ClinVar contains an entry for this variant (Variation ID: 406232). 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%. This variant disrupts the p.Cys60 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8162049, 8816997, 9452099, 10093067, 25043634). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

A variant that is likely pathogenic has been identified in the GJB1 gene. The C60R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different amino acid substitution at the same position (C60F) has been previously reported in a family with CMTX1 (Fairweather et al., 1994). The C60R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C60R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 60 of the GJB1 protein (p.Cys60Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Charcot-Marie-Tooth disease (internal data). ClinVar contains an entry for this variant (Variation ID: 406232). 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%. This variant disrupts the p.Cys60 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8162049, 8816997, 9452099, 10093067, 25043634). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel familial pathogenic mutation in gap junction protein, beta-1 gene (GJB1) associated with transient neurological deficits in a patient with X-linked Charcot-Marie-Tooth disease.	Appu M	Muscle & nerve	2014	PMID: 25043634
3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands.	-	Neuromuscular disorders : NMD	1998	PMID: 10093067
Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).	Sorour E	Human mutation	1998	PMID: 9452099
Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.	Omori Y	Molecular biology of the cell	1996	PMID: 8816997
Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).	Fairweather N	Human molecular genetics	1994	PMID: 8162049

Text-mined citations for rs1060501004 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026