NM_004004.6(GJB2):c.476A>T (p.Asp159Val) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Apr 27, 2022
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:: RCV000991848.6

Allele description [Variation Report for NM_004004.6(GJB2):c.476A>T (p.Asp159Val)]

NM_004004.6(GJB2):c.476A>T (p.Asp159Val)

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.476A>T (p.Asp159Val)

HGVS:

NC_000013.11:g.20189106T>A
NG_008358.1:g.8870A>T
NM_004004.6:c.476A>TMANE SELECT
NP_003995.2:p.Asp159Val
LRG_1350t1:c.476A>T
LRG_1350:g.8870A>T
LRG_1350p1:p.Asp159Val
NC_000013.10:g.20763245T>A
NM_004004.5:c.476A>T
P29033:p.Asp159Val

Protein change:

D159V; ASP159VAL

Links:

UniProtKB: P29033#VAR_015941; OMIM: 121011.0024; dbSNP: rs28931592

NCBI 1000 Genomes Browser:

rs28931592

Molecular consequence:

NM_004004.6:c.476A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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RecName: Full=Alpha-(1,3)-fucosyltransferase 4; AltName: Full=4-galactosyl-N-ace...
RecName: Full=Alpha-(1,3)-fucosyltransferase 4; AltName: Full=4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase; AltName: Full=ELAM-1 ligand fucosyltransferase; AltName: Full=Fucosyltransferase 4; AltName: Full=Fucosyltransferase IV; Short=Fuc-TIV; Short=FucT-IV; AltName: Full=Galactoside 3-L-fucosyltransferase
gi|226694189|sp|P22083.3|FUT4_HUMAN

Protein
LOC109279942 [Mus musculus]
LOC109279942 [Mus musculus]
Gene ID:109279942

Gene
LOC117432282 [Acipenser ruthenus]
LOC117432282 [Acipenser ruthenus]
Gene ID:117432282

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001143671	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Jun 12, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12239718, 26467025
SCV002184991	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12239718, 26061264, 14985372, 28492532
SCV002588394	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 27, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001143671

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Jun 12, 2019)

germline

clinical testing

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

SCV002184991

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 8, 2021)

germline

clinical testing

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

SCV002588394

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 27, 2022)

germline

clinical testing

Citation Link

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Exploring the clinical and epidemiological complexity of GJB2-linked deafness.

Gualandi F, Ravani A, Berto A, Sensi A, Trabanelli C, Falciano F, Trevisi P, Mazzoli M, Tibiletti MG, Cristofari E, Burdo S, Ferlini A, Martini A, Calzolari E.

Am J Med Genet. 2002 Sep 15;112(1):38-45.

PubMed [citation]

PMID:: 12239718

See all PubMed Citations (5)

Details of each submission

From Athena Diagnostics, SCV001143671.1

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

#	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

From Invitae, SCV002184991.2

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

Description

This sequence change replaces aspartic acid with valine at codon 159 of the GJB2 protein (p.Asp159Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs28931592, ExAC 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 12239718, 26061264; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17024). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 14985372), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From GeneDx, SCV002588394.2

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

Description

Reported with a second variant (phase unknown) in unrelated patients with hearing loss in published literature (Gualandi et al., 2002; Kim et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26061264, 25388846, 12239718)

#	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

Last Updated: May 7, 2024

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