NM_000166.6(GJB1):c.614A>G (p.Asn205Ser) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 16, 2024
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:: RCV000537008.12

Allele description [Variation Report for NM_000166.6(GJB1):c.614A>G (p.Asn205Ser)]

NM_000166.6(GJB1):c.614A>G (p.Asn205Ser)

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.614A>G (p.Asn205Ser)

HGVS:

NC_000023.11:g.71224321A>G
NG_008357.1:g.14110A>G
NM_000166.6:c.614A>GMANE SELECT
NM_001097642.3:c.614A>G
NP_000157.1:p.Asn205Ser
NP_001091111.1:p.Asn205Ser
LRG_245t2:c.614A>G
LRG_245:g.14110A>G
LRG_245p2:p.Asn205Ser
NC_000023.10:g.70444171A>G
NM_000166.5:c.614A>G
P08034:p.Asn205Ser

Protein change:

N205S; ASN205SER

Links:

UniProtKB: P08034#VAR_002126; OMIM: 304040.0012; dbSNP: rs104894822

NCBI 1000 Genomes Browser:

rs104894822

Molecular consequence:

NM_000166.6:c.614A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.614A>G - 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
SCV000658918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9401007, 9452099, 10071100, 12497641, 19259128, 24327141, 27544631, 28469099, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000658918

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (9)
[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

Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families.

Rouger H, LeGuern E, Birouk N, Gouider R, Tardieu S, Plassart E, Gugenheim M, Vallat JM, Louboutin JP, Bouche P, Agid Y, Brice A.

Hum Mutat. 1997;10(6):443-52.

PubMed [citation]

PMID:: 9401007

Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).

Sorour E, Upadhyaya M.

Hum Mutat. 1998;Suppl 1:S242-7. No abstract available.

PubMed [citation]

PMID:: 9452099

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000658918.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 205 of the GJB1 protein (p.Asn205Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMTX) (PMID: 9401007, 9452099, 10071100, 12497641, 19259128, 24327141, 27544631, 28469099). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10442). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. 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: Oct 20, 2024

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