NM_004004.6(GJB2):c.29T>C (p.Leu10Pro) 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:: RCV001257046.1

Allele description [Variation Report for NM_004004.6(GJB2):c.29T>C (p.Leu10Pro)]

NM_004004.6(GJB2):c.29T>C (p.Leu10Pro)

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.29T>C (p.Leu10Pro)

HGVS:

NC_000013.11:g.20189553A>G
NG_008358.1:g.8423T>C
NM_004004.6:c.29T>CMANE SELECT
NP_003995.2:p.Leu10Pro
LRG_1350t1:c.29T>C
LRG_1350:g.8423T>C
LRG_1350p1:p.Leu10Pro
NC_000013.10:g.20763692A>G

Protein change:

L10P

Links:

dbSNP: rs1959063711

NCBI 1000 Genomes Browser:

rs1959063711

Molecular consequence:

NM_004004.6:c.29T>C - 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
SCV001433597	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Uncertain significance (Aug 31, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19887791, 12865758, 26769242, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001433597

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Uncertain significance
(Aug 31, 2020)

germline

clinical testing

PubMed (4)
[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	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GJB2 and GJB6 genes: molecular study and identification of novel GJB2 mutations in the hearing-impaired Argentinean population.

Dalamón V, Lotersztein V, Béhèran A, Lipovsek M, Diamante F, Pallares N, Francipane L, Frechtel G, Paoli B, Mansilla E, Diamante V, Elgoyhen AB.

Audiol Neurootol. 2010;15(3):194-202. doi: 10.1159/000254487. Epub 2009 Nov 4.

PubMed [citation]

PMID:: 19887791

Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands.

Pandya A, Arnos KS, Xia XJ, Welch KO, Blanton SH, Friedman TB, Garcia Sanchez G, Liu MD XZ, Morell R, Nance WE.

Genet Med. 2003 Jul-Aug;5(4):295-303.

PubMed [citation]

PMID:: 12865758

See all PubMed Citations (4)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001433597.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	no	clinical testing	PubMed (4)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.29T>C, p.Leu10Pro variant in GJB2 gene is absent from population database gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This variant has been identified twice in heterozygous state and with p.Val27Ile benign variant in unknown phase in patients with hearing loss (PMID: 19887791, 12865758). Computational evidence suggested a damage impact of the mutation to the protein applying to PP3 criteria (REVELscore: 0.936). Functional studies in Hela Cells and Xenopus Laevis oocytes demonstrated difference voltage dependence and solute permeability properties in p.Leu10Pro mutant compared to WT-CX26 meeting PS3_Moderate rule (PMID: 26769242). In summary, the clinical significance of this variant is currently uncertain (PM2, PP3, PS3_Moderate)

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

Last Updated: Dec 24, 2023

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