ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.148G>A (p.Asp50Asn)

dbSNP: rs28931594
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000412852 SCV000227306 pathogenic not provided 2014-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000412852 SCV000490534 pathogenic not provided 2022-04-12 criteria provided, single submitter clinical testing Published functional studies demonstrate a defect in intracellular trafficking to the cell memberane and, most importantly, aberrant function of connexin26 hemichannels (Di et al., 2005; Lopez et al., 2013; Taki et al., 2018); Located in highly conserved first extracellular domain of connexin 26, which is a known mutational hotspot for autosomal dominant, syndromic GJB2 disorders (Richard et al., 2002; UniProt Consortium, 2017; HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21410767, 18986886, 23797419, 22951689, 27141831, 17381453, 21999526, 22643125, 15769851, 18987669, 20101161, 15823911, 15633193, 25575739, 26444850, 23924173, 25388846, 17106596, 28158657, 18412859, 16172043, 16679758, 19793313, 19175781, 28428247, 23797420, 11918723, 26810281, 30150638, 12072059, 11912510, 28981923, 29023238, 30168495, 33502802, 31705875)
Invitae RCV000412852 SCV001589150 pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 50 of the GJB2 protein (p.Asp50Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome (PMID: 11918723, 15633193, 20101161, 23924173, 25575739, 27141831). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17020). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 18987669, 23797420). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002243652 SCV002512436 pathogenic Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome 2022-02-15 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4, PM1, PM2 moderate, PM6
Mendelics RCV002247355 SCV002516478 pathogenic Mutilating keratoderma 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000018546 SCV000038828 pathogenic Autosomal dominant keratitis-ichthyosis-hearing loss syndrome 2009-03-01 no assertion criteria provided literature only
OMIM RCV000018547 SCV000038829 pathogenic Ichthyosis, hystrix-like, with hearing loss 2009-03-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000678868 SCV000805061 pathogenic Hearing loss 2006-10-17 no assertion criteria provided clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals RCV001175247 SCV001338827 pathogenic Sensorineural hearing loss disorder 2020-01-06 no assertion criteria provided clinical testing
Nemer Genomics and Translation Biomedicine Lab, American University of Beirut RCV000018546 SCV002522156 pathogenic Autosomal dominant keratitis-ichthyosis-hearing loss syndrome no assertion criteria provided clinical testing

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