NM_000166.6(GJB1):c.2T>A (p.Met1Lys) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 14, 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:: RCV001220843.8

Allele description [Variation Report for NM_000166.6(GJB1):c.2T>A (p.Met1Lys)]

NM_000166.6(GJB1):c.2T>A (p.Met1Lys)

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.2T>A (p.Met1Lys)

HGVS:

NC_000023.11:g.71223709T>A
NG_008357.1:g.13498T>A
NM_000166.6:c.2T>AMANE SELECT
NM_001097642.3:c.2T>A
NP_000157.1:p.Met1Lys
NP_001091111.1:p.Met1Lys
LRG_245t2:c.2T>A
LRG_245:g.13498T>A
LRG_245p2:p.Met1Lys
NC_000023.10:g.70443559T>A
NM_000166.5:c.2T>A

Protein change:

M1K

Links:

dbSNP: rs1602348519

NCBI 1000 Genomes Browser:

rs1602348519

Molecular consequence:

NM_000166.6:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001097642.3:c.2T>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000166.6:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.2T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001392855	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20039784, 24627108, 24958582, 25771809, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001392855

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 14, 2023)

germline

clinical testing

PubMed (5)
[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

Six new gap junction beta 1 gene mutations and their phenotypic expression in Czech patients with Charcot-Marie-Tooth disease.

Brozková D, Mazanec R, Haberlová J, Sakmaryová I, Subrt I, Seeman P.

Genet Test Mol Biomarkers. 2010 Feb;14(1):3-7. doi: 10.1089/gtmb.2009.0093.

PubMed [citation]

PMID:: 20039784

Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges.

Schabhüttl M, Wieland T, Senderek J, Baets J, Timmerman V, De Jonghe P, Reilly MM, Stieglbauer K, Laich E, Windhager R, Erwa W, Trajanoski S, Strom TM, Auer-Grumbach M.

J Neurol. 2014 May;261(5):970-82. doi: 10.1007/s00415-014-7289-8. Epub 2014 Mar 15.

PubMed [citation]

PMID:: 24627108

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001392855.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the GJB1 mRNA. The next in-frame methionine is located at codon 34. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with GJB1-related conditions (PMID: 20039784, 24627108, 24958582, 25771809; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 949392). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GJB1 function (PMID: 25771809).

#	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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