NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 21, 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:: RCV001257563.4

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:: 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
SCV001434017	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Aug 21, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1054426, 12673800, 15666300, 24158611, 12505163, 18941476, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001434017

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Aug 21, 2020)

germline

clinical testing

PubMed (7)
[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	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

The influence of mass media on the public's attitude toward fluoridation of drinking water in New Orleans.

Wallace CJ, Legett BJ, Retz PA.

J Public Health Dent. 1975 Winter;35(1):40-6. No abstract available.

PubMed [citation]

PMID:: 1054426

Spectrum of GJB2 mutations in Turkey comprises both Caucasian and Oriental variants: roles of parental consanguinity and assortative mating.

Tekin M, Duman T, Boğoçlu G, Incesulu A, Comak E, Ilhan I, Akar N.

Hum Mutat. 2003 May;21(5):552-3.

PubMed [citation]

PMID:: 12673800

See all PubMed Citations (7)

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001434017.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	2	not provided	no	clinical testing	PubMed (7)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.358_360del variant in GJB2 which leads to p.(Glu120del) change is 0,008% (17/128492 European non-Finnish alleles with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets PM2_Supporting criteria. The c.358_360del variant is predicted to cause a protein length change due to an in-frame deletion that is not located in a repetitive region applying to PM4 rule. This variant was detected in trans with at least 4 pathogenic variants among different hearing loss patients (PMID: 1054426, 12673800, 15666300, 24158611) applying to PM3_VeryStrong criteria. Functional studies showed that p.Glu120del mutant did not induce the formation of homotypic junctional channel since the conductance levels measured did not exceed the background levels in Xenopus laevis oocytes (PMID:12505163). Besides, no dye transfer (Lucifer Yellow) was observed when p.Glu120del mutant was tested in HeLa cells (PMID:18941476) meeting PS3_Moderate rule. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PM4, PM3_VeryStrong, 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		2	not provided	2	not provided

Last Updated: May 1, 2024

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