NM_004004.6(GJB2):c.148G>A (p.Asp50Asn) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000412852.16

Allele description [Variation Report for NM_004004.6(GJB2):c.148G>A (p.Asp50Asn)]

NM_004004.6(GJB2):c.148G>A (p.Asp50Asn)

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.148G>A (p.Asp50Asn)

HGVS:

NC_000013.11:g.20189434C>T
NG_008358.1:g.8542G>A
NM_004004.6:c.148G>AMANE SELECT
NP_003995.2:p.Asp50Asn
LRG_1350t1:c.148G>A
LRG_1350:g.8542G>A
LRG_1350p1:p.Asp50Asn
NC_000013.10:g.20763573C>T
NM_004004.5:c.148G>A
P29033:p.Asp50Asn

Protein change:

D50N; ASP50ASN

Links:

UniProtKB: P29033#VAR_015456; OMIM: 121011.0020; dbSNP: rs28931594

NCBI 1000 Genomes Browser:

rs28931594

Molecular consequence:

NM_004004.6:c.148G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000227306	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 31, 2014)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11912510, 11918723, 15769851, 18987669 Citation Link,
SCV000490534	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 12, 2022)	germline	clinical testing	Citation Link,
SCV001589150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11918723, 15633193, 20101161, 23924173, 25575739, 27141831, 18987669, 23797420, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000227306

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Oct 31, 2014)

germline

clinical testing

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

Citation Link,

SCV000490534

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 12, 2022)

germline

clinical testing

Citation Link,

SCV001589150

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 9, 2023)

germline

clinical testing

PubMed (9)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.

Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynänen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L.

Am J Hum Genet. 2002 May;70(5):1341-8. Epub 2002 Mar 22.

PubMed [citation]

PMID:: 11912510
PMCID:: PMC447609

Connexin interaction patterns in keratinocytes revealed morphologically and by FRET analysis.

Di WL, Gu Y, Common JE, Aasen T, O'Toole EA, Kelsell DP, Zicha D.

J Cell Sci. 2005 Apr 1;118(Pt 7):1505-14. Epub 2005 Mar 15.

PubMed [citation]

PMID:: 15769851

See all PubMed Citations (11)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227306.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000490534.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a defect in intracellular trafficking to the cell memberane and, most importantly, aberrant function of connexin26 hemichannels (Di et al., 2005; Lopez et al., 2013; Taki et al., 2018); Located in highly conserved first extracellular domain of connexin 26, which is a known mutational hotspot for autosomal dominant, syndromic GJB2 disorders (Richard et al., 2002; UniProt Consortium, 2017; HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21410767, 18986886, 23797419, 22951689, 27141831, 17381453, 21999526, 22643125, 15769851, 18987669, 20101161, 15823911, 15633193, 25575739, 26444850, 23924173, 25388846, 17106596, 28158657, 18412859, 16172043, 16679758, 19793313, 19175781, 28428247, 23797420, 11918723, 26810281, 30150638, 12072059, 11912510, 28981923, 29023238, 30168495, 33502802, 31705875)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001589150.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 50 of the GJB2 protein (p.Asp50Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome (PMID: 11918723, 15633193, 20101161, 23924173, 25575739, 27141831). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17020). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 18987669, 23797420). For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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