NM_000166.6(GJB1):c.345dup (p.His116fs) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 19, 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:: RCV003742128.1

Allele description [Variation Report for NM_000166.6(GJB1):c.345dup (p.His116fs)]

NM_000166.6(GJB1):c.345dup (p.His116fs)

Gene:

GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.345dup (p.His116fs)

HGVS:

NC_000023.11:g.71224052dup
NG_008357.1:g.13841dup
NM_000166.6:c.345dupMANE SELECT
NM_001097642.3:c.345dup
NP_000157.1:p.His116fs
NP_001091111.1:p.His116Thrfs
NP_001091111.1:p.His116fs
LRG_245t1:c.345dup
LRG_245t2:c.345dup
LRG_245:g.13841dup
LRG_245p1:p.His116Thrfs
LRG_245p2:p.His116fs
NC_000023.10:g.70443901_70443902insA
NC_000023.10:g.70443902dup
NM_001097642.2:c.345dup

Protein change:

H116fs

Molecular consequence:

NM_000166.6:c.345dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001097642.3:c.345dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004447750	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 19, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7477983, 8162049, 9364054, 9592087, 21291455, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004447750

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 19, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.

Bone LJ, Dahl N, Lensch MW, Chance PF, Kelly T, Le Guern E, Magi S, Parry G, Shapiro H, Wang S, et al.

Neurology. 1995 Oct;45(10):1863-6.

PubMed [citation]

PMID:: 7477983

Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1)

Fairweather N, Bell C, Cochrane S, Chelly J, Wang S, Mostacciuolo ML, Monaco AP, Haites NE.

Hum Mol Genet. 1994 Jan;3(1):29-34. Erratum in: Hum Mol Genet 1994 Jun;3(6):1034.

PubMed [citation]

PMID:: 8162049

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004447750.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GJB1 protein in which other variant(s) (p.Arg220*) have been determined to be pathogenic (PMID: 7477983, 8162049, 9364054, 9592087, 21291455). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with GJB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His116Thrfs*31) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acid(s) of the GJB1 protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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