NM_004004.6(GJB2):c.136G>A (p.Asp46Asn) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 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:: RCV003558394.2

Allele description [Variation Report for NM_004004.6(GJB2):c.136G>A (p.Asp46Asn)]

NM_004004.6(GJB2):c.136G>A (p.Asp46Asn)

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.136G>A (p.Asp46Asn)

HGVS:

NC_000013.11:g.20189446C>T
NG_008358.1:g.8530G>A
NM_004004.6:c.136G>AMANE SELECT
NP_003995.2:p.Asp46Asn
LRG_1350t1:c.136G>A
LRG_1350:g.8530G>A
LRG_1350p1:p.Asp46Asn
NC_000013.10:g.20763585C>T
NM_004004.5:c.136G>A

Protein change:

D46N

Links:

dbSNP: rs1064797088

NCBI 1000 Genomes Browser:

rs1064797088

Molecular consequence:

NM_004004.6:c.136G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004295456	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21484990, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295456

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss.

Bazazzadegan N, Sheffield AM, Sobhani M, Kahrizi K, Meyer NC, Van Camp G, Hilgert N, Abedini SS, Habibi F, Daneshi A, Nishimura C, Avenarius MR, Farhadi M, Smith RJ, Najmabadi H.

Am J Med Genet A. 2011 May;155A(5):1202-11. doi: 10.1002/ajmg.a.33209. Epub 2011 Apr 11. Review.

PubMed [citation]

PMID:: 21484990
PMCID:: PMC3080436

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295456.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt GJB2 protein function. ClinVar contains an entry for this variant (Variation ID: 424851). This missense change has been observed in individual(s) with autosomal dominant non-syndromic deafness (PMID: 21484990). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 46 of the GJB2 protein (p.Asp46Asn).

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

Last Updated: Nov 3, 2024

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