NM_000166.6(GJB1):c.656G>A (p.Arg219His) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 2, 2021
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:: RCV000685849.2

Allele description [Variation Report for NM_000166.6(GJB1):c.656G>A (p.Arg219His)]

NM_000166.6(GJB1):c.656G>A (p.Arg219His)

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.656G>A (p.Arg219His)

HGVS:

NC_000023.11:g.71224363G>A
NG_008357.1:g.14152G>A
NM_000166.6:c.656G>AMANE SELECT
NM_001097642.3:c.656G>A
NP_000157.1:p.Arg219His
NP_001091111.1:p.Arg219His
LRG_245t2:c.656G>A
LRG_245:g.14152G>A
LRG_245p2:p.Arg219His
NC_000023.10:g.70444213G>A
NM_000166.5:c.656G>A

Protein change:

R219H

Links:

dbSNP: rs199834862

NCBI 1000 Genomes Browser:

rs199834862

Molecular consequence:

NM_000166.6:c.656G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.656G>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
SCV000813348	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 2, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9361298, 12460545, 21280457, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813348

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 2, 2021)

germline

clinical testing

PubMed (4)
[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

Connexin32 and X-linked Charcot-Marie-Tooth disease.

Bone LJ, Deschênes SM, Balice-Gordon RJ, Fischbeck KH, Scherer SS.

Neurobiol Dis. 1997;4(3-4):221-30. Review.

PubMed [citation]

PMID:: 9361298

Diverse trafficking abnormalities of connexin32 mutants causing CMTX.

Yum SW, Kleopa KA, Shumas S, Scherer SS.

Neurobiol Dis. 2002 Oct;11(1):43-52.

PubMed [citation]

PMID:: 12460545

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000813348.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine with histidine at codon 219 of the GJB1 protein (p.Arg219His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 9361298). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect GJB1 function (PMID: 12460545, 21280457). 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: Dec 24, 2023

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