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

dbSNP: rs28931594

Total submissions: 10

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412852	SCV001589150	pathogenic	not provided	2024-07-24	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