NM_000166.6(GJB1):c.224G>A (p.Arg75Gln) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000201183.3

Allele description [Variation Report for NM_000166.6(GJB1):c.224G>A (p.Arg75Gln)]

NM_000166.6(GJB1):c.224G>A (p.Arg75Gln)

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.224G>A (p.Arg75Gln)

HGVS:

NC_000023.11:g.71223931G>A
NG_008357.1:g.13720G>A
NM_000166.6:c.224G>AMANE SELECT
NM_001097642.3:c.224G>A
NP_000157.1:p.Arg75Gln
NP_001091111.1:p.Arg75Gln
LRG_245t2:c.224G>A
LRG_245:g.13720G>A
LRG_245p2:p.Arg75Gln
NC_000023.10:g.70443781G>A
NM_000166.5:c.224G>A
P08034:p.Arg75Gln

Protein change:

R75Q

Links:

UniProtKB: P08034#VAR_002052; dbSNP: rs863224972

NCBI 1000 Genomes Browser:

rs863224972

Molecular consequence:

NM_000166.6:c.224G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.224G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease X-linked dominant 1
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED, 1; CMTX 1; Charcot-Marie-Tooth peroneal muscular atrophy, X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010549; MedGen: C0393808; Orphanet: 101075; OMIM: 302800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255687	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 4, 2013)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8829637, 12402337, 12460545, 23209285, 15006706, 10093067, 26467025
SCV005329530	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255687

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Mar 4, 2013)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005329530

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 20, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie tooth disease.

Tan CC, Ainsworth PJ, Hahn AF, MacLeod PM.

Hum Mutat. 1996;7(2):167-71. No abstract available.

PubMed [citation]

PMID:: 8829637

Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22, MPZ, and Cx32/GJB1 mutations.

Numakura C, Lin C, Ikegami T, Guldberg P, Hayasaka K.

Hum Mutat. 2002 Nov;20(5):392-8.

PubMed [citation]

PMID:: 12402337

See all PubMed Citations (8)

Details of each submission

From Athena Diagnostics, SCV000255687.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005329530.1

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

Description

The missense c.224G>A (p.Arg75Gln) variant in the GJB1 gene has been observed in individuals with X-linked Charcot-Marie-Tooth disease (Numakura, Chikahiko et al., 2002). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects GJB1 function (Abrams, Charles K et al., 2013). The variant is novel (not in any individuals) in gnomAD Exomes. It is submitted to ClinVar as Pathogenic. The amino acid Arginine at position 75 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variantThe amino acid change p.Arg75Gln in GJB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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