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NM_000166.6(GJB1):c.1A>G (p.Met1Val) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Nov 5, 2023
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:
RCV003129589.4

Allele description [Variation Report for NM_000166.6(GJB1):c.1A>G (p.Met1Val)]

NM_000166.6(GJB1):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)
HGVS:
  • NC_000023.11:g.71223708A>G
  • NG_008357.1:g.13497A>G
  • NM_000166.6:c.1A>GMANE SELECT
  • NM_001097642.3:c.1A>G
  • NP_000157.1:p.Met1Val
  • NP_001091111.1:p.Met1Val
  • NP_001091111.1:p.Met1Val
  • LRG_245t1:c.1A>G
  • LRG_245t2:c.1A>G
  • LRG_245:g.13497A>G
  • LRG_245p1:p.Met1Val
  • LRG_245p2:p.Met1Val
  • NC_000023.10:g.70443558A>G
  • NM_001097642.2:c.1A>G
Protein change:
M1V
Molecular consequence:
  • NM_000166.6:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001097642.3:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000166.6:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001097642.3:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003806283Inherited Neuropathy Consortium Ii, University Of Miami
no assertion criteria provided
Pathogenic
(Jan 7, 2020) 		germlineclinical testing

SCV004100878Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 5, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Inherited Neuropathy Consortium Ii, University Of Miami, SCV003806283.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital, SCV004100878.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)
21not providednot providedclinical testing PubMed (1)

Description

The missense variant in the first coding position, c.1A>G, in GJB1 predicts a “start loss” as coding effect and affects the translation initiation codon, p.(Met1?). This variant is absent in control population (gnomAD). It has not been reported in literature, but a hemizygous c.1A>T start loss change has been described to cause CMTX1 (PMID: 24627108). Other missense variants at the same protein position have been reported as pathogenic (PMID: 24958482, 25771809, 27844031). Functional studies showed that the start codon mutation caused loss of protein (PMID: 25771809). In silico analysis suggests this variant to be damaging (REVEL: 0.972). The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PP3_strong, PVS1_moderate, PM2_supporting).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided
2germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024