NM_000166.6(GJB1):c.462T>G (p.Tyr154Ter) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 6, 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:: RCV000822814.9

Allele description [Variation Report for NM_000166.6(GJB1):c.462T>G (p.Tyr154Ter)]

NM_000166.6(GJB1):c.462T>G (p.Tyr154Ter)

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.462T>G (p.Tyr154Ter)

HGVS:

NC_000023.11:g.71224169T>G
NG_008357.1:g.13958T>G
NM_000166.6:c.462T>GMANE SELECT
NM_001097642.3:c.462T>G
NP_000157.1:p.Tyr154Ter
NP_001091111.1:p.Tyr154Ter
LRG_245t2:c.462T>G
LRG_245:g.13958T>G
LRG_245p2:p.Tyr154Ter
NC_000023.10:g.70444019T>G
NM_000166.5:c.462T>G

Protein change:

Y154*

Links:

dbSNP: rs879254098

NCBI 1000 Genomes Browser:

rs879254098

Molecular consequence:

NM_000166.6:c.462T>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001097642.3:c.462T>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000963631	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16096811, 31948496, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000963631

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

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

Four novel connexin 32 mutations in X-linked Charcot-Marie-Tooth disease with phenotypic variability.

Karadima G, Panas M, Floroskufi P, Kalfakis N, Vassilopoulos D.

J Neurol. 2006 Feb;253(2):263-4. Epub 2005 Aug 17. No abstract available.

PubMed [citation]

PMID:: 16096811

Evidence for Cognitive Deficits in X-Linked Charcot-Marie-Tooth Disease.

Kasselimis D, Karadima G, Angelopoulou G, Breza M, Tsolakopoulos D, Potagas C, Panas M, Koutsis G.

J Int Neuropsychol Soc. 2020 Mar;26(3):294-302. doi: 10.1017/S1355617719001188. Epub 2020 Jan 17.

PubMed [citation]

PMID:: 31948496

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000963631.6

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

Description

This sequence change creates a premature translational stop signal (p.Tyr154*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 130 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 16096811, 31948496). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246097). This variant disrupts a region of the GJB1 protein in which other variant(s) (p.Ala271Trpfs*4) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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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