NM_000166.6(GJB1):c.376C>T (p.His126Tyr) AND Charcot-Marie-Tooth Neuropathy X

Clinical significance:Likely pathogenic (Last evaluated: Apr 25, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000698707.1

Allele description [Variation Report for NM_000166.6(GJB1):c.376C>T (p.His126Tyr)]

NM_000166.6(GJB1):c.376C>T (p.His126Tyr)

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.376C>T (p.His126Tyr)
HGVS:
  • NC_000023.11:g.71224083C>T
  • NG_008357.1:g.13872C>T
  • NM_000166.6:c.376C>TMANE SELECT
  • NM_001097642.3:c.376C>T
  • NP_000157.1:p.His126Tyr
  • NP_001091111.1:p.His126Tyr
  • LRG_245t2:c.376C>T
  • LRG_245:g.13872C>T
  • LRG_245p2:p.His126Tyr
  • NC_000023.10:g.70443933C>T
  • NM_000166.5:c.376C>T
  • P08034:p.His126Tyr
Protein change:
H126Y
Links:
UniProtKB: P08034#VAR_029923; dbSNP: rs879253995
NCBI 1000 Genomes Browser:
rs879253995
Molecular consequence:
  • NM_000166.6:c.376C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001097642.3:c.376C>T - 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
SCV000827387Invitaecriteria provided, single submitter
Likely pathogenic
(Apr 25, 2018)
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

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).

Panosyan FB, Laura M, Rossor AM, Pisciotta C, Piscosquito G, Burns J, Li J, Yum SW, Lewis RA, Day J, Horvath R, Herrmann DN, Shy ME, Pareyson D, Reilly MM, Scherer SS; Inherited Neuropathies Consortium—Rare Diseases Clinical Research Network (INC-RDCRN)..

Neurology. 2017 Aug 29;89(9):927-935. doi: 10.1212/WNL.0000000000004296. Epub 2017 Aug 2.

PubMed [citation]
PMID:
28768847
PMCID:
PMC5577965

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, SCV000827387.1

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

Description

This sequence change replaces histidine with tyrosine at codon 126 of the GJB1 protein (p.His126Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with X-linked Charcot-Marie-Tooth (CMTX) disease in a family (PMID: 11030070) and has been reported in several individuals affected with CMTX (PMID: 28768847). ClinVar contains an entry for this variant (Variation ID: 245904). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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: Nov 27, 2021

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