NM_000166.6(GJB1):c.622del (p.Glu208fs) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 10, 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:: RCV001951516.4

Allele description [Variation Report for NM_000166.6(GJB1):c.622del (p.Glu208fs)]

NM_000166.6(GJB1):c.622del (p.Glu208fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.622del (p.Glu208fs)

HGVS:

NC_000023.11:g.71224329del
NG_008357.1:g.14118del
NM_000166.5:c.622del
NM_000166.6:c.622delMANE SELECT
NM_001097642.3:c.622del
NP_000157.1:p.Glu208fs
NP_001091111.1:p.Glu208fs
LRG_245t2:c.622del
LRG_245:g.14118del
LRG_245p2:p.Glu208fs
NC_000023.10:g.70444179del

Protein change:

E208fs

Links:

dbSNP: rs2147946914

NCBI 1000 Genomes Browser:

rs2147946914

Molecular consequence:

NM_000166.6:c.622del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001097642.3:c.622del - 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
SCV002243911	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25614874, 27844031, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002243911

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 10, 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

The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy.

DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD, Batish SD, Lupski JR, Higgins JJ.

Mol Genet Genomic Med. 2014 Nov;2(6):522-9. doi: 10.1002/mgg3.106. Epub 2014 Aug 21.

PubMed [citation]

PMID:: 25614874
PMCID:: PMC4303222

Clinical and biophysical characterization of 19 GJB1 mutations.

Tsai PC, Yang DM, Liao YC, Chiu TY, Kuo HC, Su YP, Guo YC, Soong BW, Lin KP, Liu YT, Lee YC.

Ann Clin Transl Neurol. 2016 Nov;3(11):854-865.

PubMed [citation]

PMID:: 27844031
PMCID:: PMC5099531

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243911.3

#	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.Glu208Argfs*45) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 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 individual(s) with Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 1460272). This variant disrupts a region of the GJB1 protein in which other variant(s) (p.Arg215Pro) have been determined to be pathogenic (PMID: 27844031; 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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