NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del) AND Autosomal recessive nonsyndromic hearing loss 1A

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV000018530.53

Allele description [Variation Report for NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)]

NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)

Other names:

E118del; E120delE

HGVS:

NC_000013.10:g.20763361_20763363del
NC_000013.11:g.20189222CTC[1]
NG_008358.1:g.8749GAG[1]
NM_004004.6:c.355GAG[1]MANE SELECT
NM_004004.6:c.358_360delGAG
NP_003995.2:p.Glu120del
LRG_1350t1:c.355GAG[1]
LRG_1350:g.8749GAG[1]
LRG_1350p1:p.Glu120del
NC_000013.10:g.20763361CTC[1]
NC_000013.10:g.20763361_20763363del
NC_000013.10:g.20763361_20763363delCTC
NC_000013.11:g.20189222_20189224delCTC
NM_004004.5:c.358_360delGAG
NM_004004.6:c.355GAG[1]
NM_004004.6:c.358_360delMANE SELECT
NM_004004.6:c.358_360delGAGMANE SELECT
c.358_360delGAG
c.358_360delGAG (p.Glu120del)

Protein change:

E120del; GLU118DEL

Links:

OMIM: 121011.0007; dbSNP: rs80338947

NCBI 1000 Genomes Browser:

rs80338947

Molecular consequence:

NM_004004.6:c.355GAG[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Autosomal recessive nonsyndromic hearing loss 1A (DFNB1A)
Synonyms:: Deafness nonsyndromic, Connexin 26 linked; Deafness, autosomal recessive 1A; DFNB 1 Nonsyndromic Hearing Loss and Deafness; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009076; MedGen: C2673759; Orphanet: 90636; OMIM: 220290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038812	OMIM	no assertion criteria provided	Pathogenic (May 28, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000041045	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 16380907, 20301449
SCV000267103	Institut Pasteur du Maroc	no assertion criteria provided	Pathogenic (Apr 1, 2016)	inherited	clinical testing
SCV000599747	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (May 9, 2017)	germline	clinical testing	Citation Link,
SCV000698248	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 27, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16380907, 22695344, 12505163 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000914613	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Oct 18, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10544226, 12505163, 18941476, 16380907, 12673800 Citation Link,
SCV001193940	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19371219, 18941476, 25012701, 22695344, 12505163 Citation Link,
SCV001463374	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001810448	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059938	King Laboratory, University of Washington	criteria provided, single submitter (Abu Rayyan A et al. (Proc Natl Acad Sci U S A 2020))	Pathogenic (Aug 1, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV005051794	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	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	yes	2	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
	inherited	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	1	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Connexin 26 gene linked to a dominant deafness.

Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaïb H, Lévi-Acobas F, Weil D, Petit C.

Nature. 1998 May 28;393(6683):319-20. No abstract available.

PubMed [citation]

PMID:: 9620796

Smith RJH, Azaiez H, Booth K.

1998 Sep 28 [updated 2023 Jul 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301449

See all PubMed Citations (12)

Details of each submission

From OMIM, SCV000038812.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 Australian sisters with autosomal recessive deafness (220290), Denoyelle et al. (1997) found compound heterozygosity for deletion of codon 118 (glu) and an arg184-to-pro (R184P; 121011.0008) amino acid substitution in the GJB2 gene. One sister had moderate deafness, and the other had severe deafness.

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

From GeneReviews, SCV000041045.3

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

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

From Institut Pasteur du Maroc, SCV000267103.1

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

Description

Pathogenic

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

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000599747.1

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

#	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		2	not provided	not provided	not provided
2	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The GJB2 c.358_360delGAG (p.Glu120del) variant involves the deletion of one amino acid (Glu). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121052 control chromosomes at a frequency of 0.0000661, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported as one of the most prevalent GJB2 pathogenic variant. Functional study showed GJB2 p.glu120del could not for homotypic gap-junction channels, thus lose the junctional conductance (Bruzzone_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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

From Illumina Laboratory Services, Illumina, SCV000914613.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The GJB2 c.358_360delGAG (p.Glu120del) variant is an inframe deletion that has been reported in at least four studies in which it was found in at least 20 individuals with hearing loss, including seven homozygotes, 12 compound heterozygotes and on heterozygote in whom a second variant was not identified (Murgia et al. 2009; Tekin et al. 2003; Snoeckx et al. 2005; Mani et al. 2009). The p.Glu120del variant was absent from 120 control alleles and is reported at a frequency of 0.000135 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies conducted by two independent laboratories in Xenopus oocytes and HeLa cells revealed that compared with the wild type protein and negative control, the p.Glu120del variant resulted in the loss of gap junction channel function (Bruzzone et al. 2003; Mani et al. 2009). Further studies in HeLa cells revealed near-normal trafficking of the variant-containing protein to the cell membrane but reduced protein expression (Mani et al. 2009). Based on the collective evidence, the p.Glu120del variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Myriad Genetics, Inc., SCV001193940.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_004004.5(GJB2):c.358_360delGAG(E120del) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 19371219, 18941476, 25012701, 22695344, and 12505163. Classification of NM_004004.5(GJB2):c.358_360delGAG(E120del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Natera, Inc., SCV001463374.1

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

#	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 Genome-Nilou Lab, SCV001810448.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From King Laboratory, University of Washington, SCV002059938.1

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

Description

GJB2 c.358_360delGAG, p.E120del was previously shown to be deficient in inducing formation of junctional channels (PMID: 18941476). It is homozygous in two children from a Palestinian family with pre-lingual nonsyndromic hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and present in 20/281644 alleles on gnomAD, all heterozygotes.

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051794.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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