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NM_004004.6(GJB2):c.1A>T (p.Met1Leu) AND Nonsyndromic genetic hearing loss

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 28, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV003991034.1

Allele description [Variation Report for NM_004004.6(GJB2):c.1A>T (p.Met1Leu)]

NM_004004.6(GJB2):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)
Other names:
NM_004004.6(GJB2):c.1A>T; p.Met1Leu
HGVS:
  • NC_000013.11:g.20189581T>A
  • NG_008358.1:g.8395A>T
  • NM_004004.6:c.1A>TMANE SELECT
  • NP_003995.2:p.Met1Leu
  • LRG_1350t1:c.1A>T
  • LRG_1350:g.8395A>T
  • LRG_1350p1:p.Met1Leu
  • NC_000013.10:g.20763720T>A
  • NM_004004.5:c.1A>T
Protein change:
M1L
Links:
dbSNP: rs111033293
NCBI 1000 Genomes Browser:
rs111033293
Molecular consequence:
  • NM_004004.6:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_004004.6:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004808379ClinGen Hearing Loss Variant Curation Expert Panel
reviewed by expert panel

(Clingen Hl Acmg Specifications Cdh23 Coch Gjb2 Kcnq4 Myo6 Myo7a Slc26a4 Tecta Ush2a V2)		Likely Pathogenic
(Mar 28, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV004808379.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The 1A>T (p.Met1Leu) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 2; 10.18.2023).

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

Last Updated: Sep 29, 2024