NM_004004.6(GJB2):c.35del (p.Gly12fs) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 20, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000211775.12

Allele description [Variation Report for NM_004004.6(GJB2):c.35del (p.Gly12fs)]

NM_004004.6(GJB2):c.35del (p.Gly12fs)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.35del (p.Gly12fs)

Other names:

NM_004004.5(GJB2):c.35delG(p.Gly12Valfs); NM_004004.5(GJB2):c.35delG

HGVS:

NC_000013.11:g.20189552del
NG_008358.1:g.8429del
NM_004004.6:c.35delMANE SELECT
NP_003995.2:p.Gly12fs
LRG_1350t1:c.35del
LRG_1350:g.8429del
LRG_1350p1:p.Gly12fs
NC_000013.10:g.20763686del
NC_000013.10:g.20763686delC
NC_000013.10:g.20763686delC
NC_000013.10:g.20763691del
NC_000013.10:g.20763691del
NC_000013.10:g.20763691delC
NC_000013.11:g.20189547delC
NM_004004.5:c.35delG
NM_004004.6:c.35delGMANE SELECT
c.35delG
c.35delG (p.Gly12Valfs*2)
p.(Gly12Valfs*2)
p.Gly12Valfs*2
p.Gly12ValfsX2
p.Gly12fs

Protein change:

G12fs

Links:

OMIM: 121011.0005; dbSNP: rs80338939

NCBI 1000 Genomes Browser:

rs80338939

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

Recent activity

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translation elongation factor 1-alpha, partial [Leucodecton inspersum]
translation elongation factor 1-alpha, partial [Leucodecton inspersum]
gi|1216722871|gb|ASM41768.1|

Protein
translation elongation factor 1-alpha, partial [Austrotrema bicinctulum]
translation elongation factor 1-alpha, partial [Austrotrema bicinctulum]
gi|1216722837|gb|ASM41751.1|

Protein
Homo sapiens cDNA clone IMAGE:5260228
Homo sapiens cDNA clone IMAGE:5260228
gi|29791446|gb|BC050357.1|

Nucleotide
Homo sapiens ADAM metallopeptidase with thrombospondin type 1 motif, 9, mRNA (cD...
Homo sapiens ADAM metallopeptidase with thrombospondin type 1 motif, 9, mRNA (cDNA clone IMAGE:4249695)
gi|34194179|gb|BC026271.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000840537	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (ClinGen HL ACMG Specifications v1)	Pathogenic (Sep 20, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26969326, 25999548 Citation Link,
SCV001434024	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 31, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000840537

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Sep 20, 2018)

germline

curation

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

Citation Link,

SCV001434024

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 31, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	curation
Caucasian	germline	yes	79	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.

Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, Ephraim SS, Shibata SB, Booth KT, Campbell CA, Ranum PT, Weaver AE, Black-Ziegelbein EA, Wang D, Azaiez H, Smith RJH.

Hum Genet. 2016 Apr;135(4):441-450. doi: 10.1007/s00439-016-1648-8. Epub 2016 Mar 11.

PubMed [citation]

PMID:: 26969326
PMCID:: PMC4796320

Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review.

Tsukada K, Nishio SY, Hattori M, Usami S.

Ann Otol Rhinol Laryngol. 2015 May;124 Suppl 1:61S-76S. doi: 10.1177/0003489415575060. Review.

PubMed [citation]

PMID:: 25999548

See all PubMed Citations (3)

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV000840537.4

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

Description

The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1.

#	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 INGEBI, INGEBI / CONICET, SCV001434024.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	79	not provided	no	clinical testing	PubMed (1)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		79	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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