NM_000166.6(GJB1):c.132G>C (p.Trp44Cys) AND Charcot-Marie-Tooth Neuropathy X

Clinical significance:Likely pathogenic (Last evaluated: Nov 29, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001068519.2

Allele description [Variation Report for NM_000166.6(GJB1):c.132G>C (p.Trp44Cys)]

NM_000166.6(GJB1):c.132G>C (p.Trp44Cys)

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.132G>C (p.Trp44Cys)
HGVS:
  • NC_000023.11:g.71223839G>C
  • NG_008357.1:g.13628G>C
  • NM_000166.6:c.132G>CMANE SELECT
  • NM_001097642.3:c.132G>C
  • NP_000157.1:p.Trp44Cys
  • NP_001091111.1:p.Trp44Cys
  • LRG_245t2:c.132G>C
  • LRG_245:g.13628G>C
  • LRG_245p2:p.Trp44Cys
  • NC_000023.10:g.70443689G>C
  • NM_000166.5:c.132G>C
Protein change:
W44C
Links:
dbSNP: rs879253935
NCBI 1000 Genomes Browser:
rs879253935
Molecular consequence:
  • NM_000166.6:c.132G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001097642.3:c.132G>C - 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
SCV001233635Invitaecriteria provided, single submitter
Likely pathogenic
(Nov 29, 2019)
germlineclinical testing

PubMed (2)
[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

[Clinical-genetic characteristics of hereditary motor-sensory neuropathy type 1 X].

Sharkova IV, Milovidova TB, Dadali EL, Poliakov AV.

Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(7):42-7. Russian.

PubMed [citation]
PMID:
23011429

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001233635.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces tryptophan with cysteine at codon 44 of the GJB1 protein (p.Trp44Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary motor sensory neuropathy (PMID: 23011429). ClinVar contains an entry for this variant (Variation ID: 245761). 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. This variant disrupts the p.Trp44 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 23011429), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 30, 2021

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