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

dbSNP: rs80338947

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211776	SCV000061503	pathogenic	Rare genetic deafness	2022-08-26	criteria provided, single submitter	clinical testing	The p.Glu120del variant in GJB2 has been reported in the homozygous state in more than ten probands and in the compound heterozygous state with another GJB2 pathogenic variant in more than nine probands with hearing loss (Najmabadi 2005, Tekin 2003, Hismi 2006, Marlin 2005, Mani 2008, LMM data). This variant has been identified in 17/126016 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338947); however, its frequency is low enough to be consistent with a recessive carrier frequency for autosomal recessive nonsyndromic hearing loss. Functional studies indicate that the channels formed by the p.Glu120del mutant protein are inactive (Mani 2008). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PS2_Supporting
Genetic Services Laboratory, University of Chicago	RCV000146018	SCV000193170	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018530	SCV000599747	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000520132	SCV000617686	pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in the cytoplasmic loop, a non-repeat region; Published functional studies demonstrate c.358_360delGAG impairs the function of gap channels (Bruzzone et al., 2003; Mani et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 29485809, 15070423, 11438992, 20609484, 10544226, 12673800, 15666300, 15967879, 16712961, 12505163, 18941476, 27573290, 27177978, 29501291, 31160754, 32747562, 33096615, 31589614, 33105617, 34581455, 34695157)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018530	SCV000698248	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-12-27	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000520132	SCV000841706	pathogenic	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000018530	SCV000914613	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-10-18	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520132	SCV000945066	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This variant, c.358_360del, results in the deletion of 1 amino acid(s) of the GJB2 protein (p.Glu120del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80338947, gnomAD 0.01%). This variant has been observed in individuals with autosomal recessive deafness (PMID: 10544226, 11438992, 15070423, 16712961, 18941476, 20553101, 20609484, 25214170). ClinVar contains an entry for this variant (Variation ID: 17006). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB2 function (PMID: 12505163, 18941476). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000018530	SCV001193940	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-20	criteria provided, single submitter	clinical testing	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.
INGEBI, INGEBI / CONICET	RCV001257563	SCV001434017	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000520132	SCV001747686	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000018530	SCV001810448	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-22	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000018530	SCV002059938	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-08-01	criteria provided, single submitter	research	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.
Fulgent Genetics, Fulgent Genetics	RCV002496401	SCV002810521	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-03-26	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000018530	SCV005051794	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-02-01	criteria provided, single submitter	curation
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000520132	SCV005199406	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000018530	SCV000038812	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	1998-05-28	no assertion criteria provided	literature only
GeneReviews	RCV000018530	SCV000041045	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Institut Pasteur du Maroc	RCV000018530	SCV000267103	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-04-01	no assertion criteria provided	clinical testing	Pathogenic
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678881	SCV000805074	pathogenic	Hearing loss	2015-10-08	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000018530	SCV001463374	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing