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

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 22, 2023
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:
RCV000698707.6

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000827387Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Oct 22, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

A family with X-linked dominant Charcot-Marie-Tooth caused by a connexin32 mutation.

Verhelst HE, Lofgren A, Van Coster RN.

Eur J Paediatr Neurol. 2000;4(5):235-8.

PubMed [citation]
PMID:
11030070

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
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000827387.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 126 of the GJB1 protein (p.His126Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 11030070, 28768847, 32376792). ClinVar contains an entry for this variant (Variation ID: 245904). 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. 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: Feb 20, 2024