ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.355_357GAG[1] (p.Glu120del) (rs80338947)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211776 SCV000061503 pathogenic Rare genetic deafness 2017-06-06 criteria provided, single submitter clinical testing The p.Glu120del variant in GJB2 has been reported in the homozygous state in mor e than ten probands and in the compound heterozygous state with another GJB2 pat hogenic variant in more than nine probands with hearing loss (Najmabadi 2005, Te kin 2003, Hismi 2006, Marlin 2005, Mani 2008, LMM data). This variant has been i dentified in 17/126016 European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338947); however, its freque ncy is low enough to be consistent with a recessive carrier frequency for autoso mal recessive nonsyndromic hearing loss. Functional studies indicate that the c hannels formed by the p.Glu120del mutant protein are inactive (Mani 2008). In su mmary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PS2_Supp orting
Genetic Services Laboratory, University of Chicago RCV000146018 SCV000193170 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018530 SCV000599747 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
GeneDx RCV000520132 SCV000617686 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing The c.358_360delGAG variant has been published previously in association with hearing loss (Murgia et al., 1999; Roux et al., 2004; Mani et al., 2009; Mahdieh et al., 2010). The variant is observed in 17/126016 (0.014%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The c.358_360delGAG variant results in the in-frame deletion of Glutamic acid 120, a residue that is conserved in mammals. Functional studies have shown that c.358_360delGAG impairs the function of gap channels (Bruzzone et al., 2003; Mani et al., 2009). In summary, we consider this variant to be pathogenic.
Counsyl RCV000018530 SCV000678103 pathogenic Deafness, autosomal recessive 1A 2015-04-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018530 SCV000698248 pathogenic Deafness, autosomal recessive 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 Inc RCV000520132 SCV000841706 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018530 SCV000914613 pathogenic Deafness, autosomal recessive 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.
Invitae RCV000520132 SCV000945066 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing This variant, c.358_360delGAG, 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, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another GJB2 variant in individuals affected with deafness (PMID: 16712961, 15070423, 10544226, 11438992, 20609484, 18941476, 25214170, 20553101). ClinVar contains an entry for this variant (Variation ID: 17006). This variant has been reported to affect GJB2 protein function (PMID: 12505163, 18941476). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018530 SCV000038812 pathogenic Deafness, autosomal recessive 1A 1998-05-28 no assertion criteria provided literature only
GeneReviews RCV000018530 SCV000041045 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Institut Pasteur du Maroc RCV000018530 SCV000267103 pathogenic Deafness, autosomal recessive 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

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