NM_000166.6(GJB1):c.343dup (p.Leu115fs) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 30, 2016
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:: RCV000476759.7

Allele description [Variation Report for NM_000166.6(GJB1):c.343dup (p.Leu115fs)]

NM_000166.6(GJB1):c.343dup (p.Leu115fs)

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.343dup (p.Leu115fs)

HGVS:

NC_000023.11:g.71224050dup
NG_008357.1:g.13839dup
NM_000166.6:c.343dupMANE SELECT
NM_001097642.3:c.343dup
NP_000157.1:p.Leu115fs
NP_001091111.1:p.Leu115fs
LRG_245t2:c.343dup
LRG_245:g.13839dup
LRG_245p2:p.Leu115fs
NC_000023.10:g.70443895_70443896insC
NC_000023.10:g.70443900dup
NM_000166.5:c.343dupC

Protein change:

L115fs

Links:

dbSNP: rs1555937150

NCBI 1000 Genomes Browser:

rs1555937150

Molecular consequence:

NM_000166.6:c.343dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001097642.3:c.343dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Homo sapiens keratin associated protein 22-1, mRNA (cDNA clone MGC:126731 IMAGE:...
Homo sapiens keratin associated protein 22-1, mRNA (cDNA clone MGC:126731 IMAGE:8069188), complete cds
gi|75516698|gb|BC101682.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544769	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 30, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8162049, 9364054, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544769

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 30, 2016)

germline

clinical testing

PubMed (3)
[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

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

Altered trafficking of mutant connexin32.

Deschênes SM, Walcott JL, Wexler TL, Scherer SS, Fischbeck KH.

J Neurosci. 1997 Dec 1;17(23):9077-84.

PubMed [citation]

PMID:: 9364054
PMCID:: PMC6573613

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544769.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant disrupts the final 169 amino acids, or about 60%, of the GJB1 protein. In addition, a different truncation downstream of this variant (p.Arg220*) has been determined to be pathogenic (PMID: 8162049, 9364054). This suggests that deletion of this region of the GJB1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with a GJB1-related disease. This sequence change inserts 1 nucleotide in exon 2 of the GJB1 mRNA (c.343dupC), causing a frameshift at codon 115. This creates a premature translational stop signal in the last exon of the GJB1 mRNA (p.Leu115Profs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acids 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: Sep 29, 2024

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