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NM_000166.6(GJB1):c.548G>A (p.Arg183His) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 13, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000654852.12

Allele description [Variation Report for NM_000166.6(GJB1):c.548G>A (p.Arg183His)]

NM_000166.6(GJB1):c.548G>A (p.Arg183His)

Gene:
GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xq13.1
Genomic location:
Preferred name:
NM_000166.6(GJB1):c.548G>A (p.Arg183His)
HGVS:
  • NC_000023.11:g.71224255G>A
  • NG_008357.1:g.14044G>A
  • NM_000166.6:c.548G>AMANE SELECT
  • NM_001097642.3:c.548G>A
  • NP_000157.1:p.Arg183His
  • NP_001091111.1:p.Arg183His
  • LRG_245t2:c.548G>A
  • LRG_245:g.14044G>A
  • LRG_245p2:p.Arg183His
  • NC_000023.10:g.70444105G>A
  • NM_000166.5:c.548G>A
Protein change:
R183H
Links:
dbSNP: rs1555937233
NCBI 1000 Genomes Browser:
rs1555937233
Molecular consequence:
  • NM_000166.6:c.548G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001097642.3:c.548G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth Neuropathy X
Identifiers:
MedGen: CN118851

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000776754Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 13, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular genetic analysis of the GJB1 gene: a study of six mutations.

Kochański A, Kabzińska D.

J Appl Genet. 2004;45(1):95-100.

PubMed [citation]
PMID:
14960772

Mutation screening of Cx32 in Han Chinese patients with Charcot-Marie-Tooth disease.

Zhang RX, Luo W, Zi XH, Xia K, Cai F, Xiao JF, Zhao GH, Zhang FF, Shen L, Jiang H, Tang BS.

Beijing Da Xue Xue Bao Yi Xue Ban. 2005 Feb 18;37(1):68-71.

PubMed [citation]
PMID:
15719046
See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000776754.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

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). 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%. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024