Submissions for variant NM_004004.6(GJB2):c.439G>A (p.Glu147Lys)

gnomAD frequency: 0.00004  dbSNP: rs767178508

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409580	SCV000487518	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-02-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000411084	SCV000487519	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000488996	SCV000576949	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15253766, 26188157, 25149764, 29921236, 30168495, 29542069, 14676473, 19371219, 14985372, 16380907, 16125251, 17567887, 20022641, 21465647, 26346709, 25388846, 26043044, 30094485, 31215297, 30989077, 30344259, 21131880, 31160754, 30275481, 32645618, 33096615, 31589614, 29871260, 31541171, 31827275)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506862	SCV000603819	pathogenic	not specified	2016-08-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825565	SCV000966892	pathogenic	Rare genetic deafness	2018-09-21	criteria provided, single submitter	clinical testing	The p.Glu147Lys variant in GJB2 has been reported in 8 individuals with hearing loss, including 3 homozygotes and 5 individuals who were compound heterozygous f or a second pathogenic variant (Cryns 2004, de Oliveira 2007, Dodson 2011, Frei 2004, Gravina 2010, Lin 2011, Snoeckx 2005, Zheng 2015). In addition, the varian t segregated in the homozygous state in two affected siblings in one family (Fre i 2004). This variant is present in 3/245794 total chromosomes by gnomAD (http:/ /gnomad.broadinstitute.org), which is low enough to be consistent with a recessi ve carrier frequency. Computational prediction tools and conservation analysis s uggest an impact to the protein. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1_Moderate, PP3.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000409580	SCV001244785	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-08-04	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_004004.5(GJB2):c.439G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from a glutamic acid to a lysine at position 147, NP_003995.2(GJB2):p.(Glu147Lys). The glutamic acid at this position has very high conservation (100 vertebrates, UCSC) and in silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster).This variant is present in the gnomAD population database at a frequency of 0.001% and it has been previously reported in patients with autosomal recessive deafness (ClinVar, Frei, K. et al. (2004) and Cryns, K. et al. (2004)).It is situated in the third transmembrane domain, which has been shown to be essential for protein function (Frei K. et al. (2004). Based on current information and in association with the NM_004004.5(GJB2):c.35delG deletion variant, this variant has been classified as PATHOGENIC.The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness.
CeGaT Center for Human Genetics Tuebingen	RCV000488996	SCV001245648	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001257565	SCV001434019	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 c.439G>A, p.(Glu147Lys) was observed only once in South Asian, Latino and European non-Finnish populations from Genome Aggregation Database (http://gnomad.broadinstitute.org), meeting PM2 criteria. This was detected in trans with at least 4 different pathogenic variants applying to PM3_VeryStrong rule (PMID: 14676473, 21131880, 14985372, 21465647, 26043044). Besides, it segregated in three affected siblings with congenital moderate-profound hearing loss meeting PP1_Moderate criteria (PMID:14676473). Computational evidence predicted a damage impact of the mutation to the protein (REVEL score: 0,94; PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PM3_VeryStrong, PP1_Moderate and PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000488996	SCV002228260	pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the GJB2 protein (p.Glu147Lys). This variant is present in population databases (rs767178508, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 14676473, 21465647, 30168495, 30344259). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 371709). 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. For these reasons, this variant has been classified as Pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000409580	SCV000902312	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000409580	SCV001463367	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001257565	SCV002754542	pathogenic	Nonsyndromic genetic hearing loss	2022-05-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735500	SCV005355631	pathogenic	GJB2-related disorder	2024-04-01	no assertion criteria provided	clinical testing	The GJB2 c.439G>A variant is predicted to result in the amino acid substitution p.Glu147Lys. This variant was reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Frei et al. 2004. PubMed ID: 14676473; Singh et al. 2018. PubMed ID: 30168495; Plevova et al. 2018. PubMed ID: 30344259; Table S2, Yuan et al. 2019. PubMed ID: 31541171; Downie et al. 2019. PubMed ID: 31827275). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.