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NM_004004.6(GJB2):c.487A>C (p.Met163Leu) AND Nonsyndromic genetic hearing loss

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 4, 2020
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:
RCV001251627.9

Allele description [Variation Report for NM_004004.6(GJB2):c.487A>C (p.Met163Leu)]

NM_004004.6(GJB2):c.487A>C (p.Met163Leu)

Gene:
GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q12.11
Genomic location:
Preferred name:
NM_004004.6(GJB2):c.487A>C (p.Met163Leu)
HGVS:
  • NC_000013.11:g.20189095T>G
  • NG_008358.1:g.8881A>C
  • NM_004004.6:c.487A>CMANE SELECT
  • NP_003995.2:p.Met163Leu
  • NP_003995.2:p.Met163Leu
  • LRG_1350t1:c.487A>C
  • LRG_1350:g.8881A>C
  • LRG_1350p1:p.Met163Leu
  • NC_000013.10:g.20763234T>G
  • NM_004004.5:c.487A>C
Protein change:
M163L
Links:
dbSNP: rs80338949
NCBI 1000 Genomes Browser:
rs80338949
Molecular consequence:
  • NM_004004.6:c.487A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Nonsyndromic genetic hearing loss
Synonyms:
Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:
MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001427361INGEBI, INGEBI / CONICET
criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)		Uncertain significance
(Aug 4, 2020) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
Caucasiangermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

A novel M163L mutation in connexin 26 causing cell death and associated with autosomal dominant hearing loss.

Matos TD, Caria H, Simões-Teixeira H, Aasen T, Dias O, Andrea M, Kelsell DP, Fialho G.

Hear Res. 2008 Jun;240(1-2):87-92. doi: 10.1016/j.heares.2008.03.004. Epub 2008 Apr 3.

PubMed [citation]
PMID:
18472371

Spectrum and frequency of GJB2 mutations in a cohort of 264 Portuguese nonsyndromic sensorineural hearing loss patients.

Matos TD, Simões-Teixeira H, Caria H, Gonçalves AC, Chora J, Correia Mdo C, Moura C, Rosa H, Monteiro L, O'Neill A, Dias Ó, Andrea M, Fialho G.

Int J Audiol. 2013 Jul;52(7):466-71. doi: 10.3109/14992027.2013.783719. Epub 2013 May 13.

PubMed [citation]
PMID:
23668481
See all PubMed Citations (4)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001427361.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian1not providednoclinical testing PubMed (4)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel (HL-EP) specific criteria: the c.487A>C, p.Met163Leu variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. Computational evidence is not enough to meet neither PP3 nor BP4 rules, since REVEL score is 0.534. This variant has been detected in a family case in the proband and her affected mother. In the same report, the variant was studied in HeLa cells demonstrating that the mutant protein p.Met163Leu had defective trafficking to the plasma membrane and was associated with increased cell death (PMID:18472371). Since the functional studies performed in that report were not the specified by the HL-EP, the evidence strength has been downgraded to PS3_Supporting. Besides, the p.Met163Leu change has beed identified in heterozygous state in two hearing loss patients (PMID: 23668481;19887791) meeting PS4_Supporting rule. In summary, the clinical significance of this variant is currently uncertain (PM2, PS3_Supporting, PS4_Supporting).

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

Last Updated: Nov 10, 2024