NM_000166.6(GJB1):c.476G>A (p.Gly159Asp) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 27, 2022
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:: RCV001869227.6

Allele description [Variation Report for NM_000166.6(GJB1):c.476G>A (p.Gly159Asp)]

NM_000166.6(GJB1):c.476G>A (p.Gly159Asp)

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.476G>A (p.Gly159Asp)

HGVS:

NC_000023.11:g.71224183G>A
NG_008357.1:g.13972G>A
NM_000166.6:c.476G>AMANE SELECT
NM_001097642.3:c.476G>A
NP_000157.1:p.Gly159Asp
NP_001091111.1:p.Gly159Asp
LRG_245t2:c.476G>A
LRG_245:g.13972G>A
LRG_245p2:p.Gly159Asp
NC_000023.10:g.70444033G>A
NM_000166.5:c.476G>A

Protein change:

G159D

Links:

dbSNP: rs1602349446

NCBI 1000 Genomes Browser:

rs1602349446

Molecular consequence:

NM_000166.6:c.476G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.476G>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
SCV002171968	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28768847, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002171968

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 27, 2022)

germline

clinical testing

PubMed (2)
[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

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).

Panosyan FB, Laura M, Rossor AM, Pisciotta C, Piscosquito G, Burns J, Li J, Yum SW, Lewis RA, Day J, Horvath R, Herrmann DN, Shy ME, Pareyson D, Reilly MM, Scherer SS; Inherited Neuropathies Consortium—Rare Diseases Clinical Research Network (INC-RDCRN)..

Neurology. 2017 Aug 29;89(9):927-935. doi: 10.1212/WNL.0000000000004296. Epub 2017 Aug 2.

PubMed [citation]

PMID:: 28768847
PMCID:: PMC5577965

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002171968.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 637591). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 28768847). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 159 of the GJB1 protein (p.Gly159Asp). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

ClinVar

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