NM_004004.6(GJB2):c.503A>G (p.Lys168Arg) AND Nonsyndromic genetic hearing loss

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 31, 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:: RCV001257049.1

Allele description [Variation Report for NM_004004.6(GJB2):c.503A>G (p.Lys168Arg)]

NM_004004.6(GJB2):c.503A>G (p.Lys168Arg)

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.503A>G (p.Lys168Arg)

HGVS:

NC_000013.11:g.20189079T>C
NG_008358.1:g.8897A>G
NM_004004.6:c.503A>GMANE SELECT
NP_003995.2:p.Lys168Arg
LRG_1350t1:c.503A>G
LRG_1350:g.8897A>G
LRG_1350p1:p.Lys168Arg
NC_000013.10:g.20763218T>C
NM_004004.5:c.503A>G
P29033:p.Lys168Arg
c.503A>G

Protein change:

K168R

Links:

UniProtKB: P29033#VAR_057959; dbSNP: rs200104362

NCBI 1000 Genomes Browser:

rs200104362

Molecular consequence:

NM_004004.6:c.503A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001433600	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Uncertain significance (Aug 31, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17567889, 19125024, 20381175, 20497192, 21728791, 24156272, 19887791, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433600

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Uncertain significance
(Aug 31, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Caucasian	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular study in Brazilian cochlear implant recipients.

Christiani TV, Alexandrino F, de Oliveira CA, Amantini RC, Bevilacqua MC, Filho OA, Porto P, Sartorato EL.

Am J Med Genet A. 2007 Jul 15;143A(14):1580-2.

PubMed [citation]

PMID:: 17567889

Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.

Batissoco AC, Abreu-Silva RS, Braga MC, Lezirovitz K, Della-Rosa V, Alfredo T Jr, Otto PA, Mingroni-Netto RC.

Ear Hear. 2009 Feb;30(1):1-7. doi: 10.1097/AUD.0b013e31819144ad.

PubMed [citation]

PMID:: 19125024

See all PubMed Citations (8)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	5	not provided	no	clinical testing	PubMed (8)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.503A>G, p.(Lys168Arg) variant in GJB2 gene is 0,015% (10/35418 Latino alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2_Supporting rule. Computational evidence predicted a pathogenic effect of the mutation to the protein (REVELscore: 0.720) applying to PP3 criteria. The p.(Lys168Arg) change has been identified only in heterozygous state in several patients (PMID: 17567889, 19125024, 20381175, 20497192, 21728791, 24156272, 19887791). Therefore, the clinical significance of this variant is currently uncertain (PM2_Supporting, PP3).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		5	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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