ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.148G>A (p.Asp50Asn) (rs28931594)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000412852 SCV000227306 pathogenic not provided 2014-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000412852 SCV000490534 pathogenic not provided 2020-04-16 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; Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); 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)
Invitae RCV000412852 SCV001589150 pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 50 of the GJB2 protein (p.Asp50Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with keratitis-ichthyosis-deafness syndrome (PMID: 23924173, 25575739, 11918723, 15633193), and was shown to arise de novo in several affected individuals (PMID: 27141831, 20101161, 15633193). ClinVar contains an entry for this variant (Variation ID: 17020). Experimental studies have shown that this missense change disrupts the activity and regulation of the connexin 26 channel (PMID: 23797420, 18987669). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018546 SCV000038828 pathogenic Keratitis-ichthyosis-deafness syndrome, autosomal dominant 2009-03-01 no assertion criteria provided literature only
OMIM RCV000018547 SCV000038829 pathogenic Hystrix-like ichthyosis with deafness 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 2020-01-06 no assertion criteria provided clinical testing

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