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NM_000166.6(GJB1):c.580A>C (p.Met194Leu) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 19, 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:
RCV003582071.2

Allele description [Variation Report for NM_000166.6(GJB1):c.580A>C (p.Met194Leu)]

NM_000166.6(GJB1):c.580A>C (p.Met194Leu)

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.580A>C (p.Met194Leu)
HGVS:
  • NC_000023.11:g.71224287A>C
  • NG_008357.1:g.14076A>C
  • NM_000166.6:c.580A>CMANE SELECT
  • NM_001097642.3:c.580A>C
  • NP_000157.1:p.Met194Leu
  • NP_001091111.1:p.Met194Leu
  • NP_001091111.1:p.Met194Leu
  • LRG_245t1:c.580A>C
  • LRG_245t2:c.580A>C
  • LRG_245:g.14076A>C
  • LRG_245p1:p.Met194Leu
  • LRG_245p2:p.Met194Leu
  • NC_000023.10:g.70444137A>C
  • NM_001097642.2:c.580A>C
Protein change:
M194L
Molecular consequence:
  • NM_000166.6:c.580A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001097642.3:c.580A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Charcot-Marie-Tooth Neuropathy X
Identifiers:
MedGen: CN118851

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004335756Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 19, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.

Silander K, Meretoja P, Pihko H, Juvonen V, Issakainen J, Aula P, Savontaus ML.

Hum Genet. 1997 Sep;100(3-4):391-7.

PubMed [citation]
PMID:
9272161

Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing.

Drew AP, Zhu D, Kidambi A, Ly C, Tey S, Brewer MH, Ahmad-Annuar A, Nicholson GA, Kennerson ML.

Mol Genet Genomic Med. 2015 Mar;3(2):143-54. doi: 10.1002/mgg3.126. Epub 2015 Jan 14.

PubMed [citation]
PMID:
25802885
PMCID:
PMC4367087
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004335756.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 194 of the GJB1 protein (p.Met194Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. This variant disrupts the p.Met194 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9272161, 25802885). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024