ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.439G>A (p.Glu147Lys) (rs767178508)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409580 SCV000487518 likely pathogenic Deafness, autosomal recessive 1A 2016-02-18 criteria provided, single submitter clinical testing
Counsyl RCV000411084 SCV000487519 likely pathogenic Deafness, autosomal dominant 3a 2016-02-18 criteria provided, single submitter clinical testing
GeneDx RCV000488996 SCV000576949 pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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, 31541171, 31827275, 31160754, 30275481, 33096615, 31589614, 29871260)
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, Partners HealthCare 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:/ /, 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 Deafness, autosomal recessive 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 Praxis fuer Humangenetik Tuebingen RCV000488996 SCV001245648 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257565 SCV001434019 pathogenic Nonsyndromic hearing loss and deafness 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 (, 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.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000409580 SCV000902312 likely pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Natera, Inc. RCV000409580 SCV001463367 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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