Submissions for variant NM_004004.6(GJB2):c.475G>A (p.Asp159Asn)

dbSNP: rs373684994

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000505527	SCV000599754	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001755751	SCV001986169	uncertain significance	not provided	2020-11-19	criteria provided, single submitter	clinical testing	Observed in patients with hearing loss in published literature; limited information is available for these patients, and the variant was observed with no other GJB2 variant in at least one case (Cryns et al., 2004; Snoeckx et al., 2005; Dai et al., 2009; Qing et al., 2015); In vitro functional studies suggest the variant does not affect voltage-activation of hemichannels; however, data was not available for review (Daniel et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 19366456, 25493717, 16380907, 14985372, 25388846, 17077310, 17666888, 17041943)
Myriad Genetics, Inc.	RCV000505527	SCV002060345	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2021-11-09	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.475G>A(D159N) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. D159N has been observed in cases with relevant disease (PMID: 19366456, 17666888, 14985372). Functional assessments of this variant are available in the literature (PMID: 17077310). D159N has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.475G>A(D159N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282187	SCV002570748	uncertain significance	not specified	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.475G>A (p.Asp159Asn) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (8.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.475G>A has been reported in the literature in cohorts with hearing loss (example, Cryns_2004, Snoeckx_2005, Putcha_2007, Dai_2009, Qing_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001755751	SCV005835542	uncertain significance	not provided	2024-05-02	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 159 of the GJB2 protein (p.Asp159Asn). This variant is present in population databases (rs373684994, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 16380907, 17666888, 25493717). ClinVar contains an entry for this variant (Variation ID: 438618). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.