NM_000166.6(GJB1):c.423C>G (p.Phe141Leu) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 17, 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:: RCV003993995.2

Allele description [Variation Report for NM_000166.6(GJB1):c.423C>G (p.Phe141Leu)]

NM_000166.6(GJB1):c.423C>G (p.Phe141Leu)

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.423C>G (p.Phe141Leu)

HGVS:

NC_000023.11:g.71224130C>G
NG_008357.1:g.13919C>G
NM_000166.6:c.423C>GMANE SELECT
NM_001097642.3:c.423C>G
NP_000157.1:p.Phe141Leu
NP_001091111.1:p.Phe141Leu
LRG_245t2:c.423C>G
LRG_245:g.13919C>G
LRG_245p2:p.Phe141Leu
NC_000023.10:g.70443980C>G
NM_000166.5:c.423C>G

Protein change:

F141L

Links:

dbSNP: rs1555937180

NCBI 1000 Genomes Browser:

rs1555937180

Molecular consequence:

NM_000166.6:c.423C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.423C>G - 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
SCV004812283	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9401007, 11571214, 25741868
SCV005086773	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9401007, 11571214, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812283

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 4, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005086773

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (3)
[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	yes	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

Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.

Dubourg O, Tardieu S, Birouk N, Gouider R, Léger JM, Maisonobe T, Brice A, Bouche P, LeGuern E.

Brain. 2001 Oct;124(Pt 10):1958-67.

PubMed [citation]

PMID:: 11571214

See all PubMed Citations (3)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812283.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change in GJB1 is predicted to replace phenylalanine with leucine at codon 141, p.(Phe141Leu). The phenylalanine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane 3 domain. There is a small physicochemical difference between phenylalanine and leucine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two families with Charcot-Marie-Tooth neuropathy and segregates with disease extensively in at least one of the reported families (PMID: 9401007, 11571214). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Supporting, PM2_Supporting, PP3.

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086773.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth neuropathy 1 (MIM#302800). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Some female variant carriers may be asymptomatic (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been reported for affected males and female variant carriers (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated transmembrane domain 3 (PMID: 9401007). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by one clinical diagnostic laboratory and has been reported in two individuals or families with Charcot-Marie-Tooth disease (ClinVar; PMIDs: 9401007, 11571214). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Aug 4, 2024

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