ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.511G>A (p.Ala171Thr)

gnomAD frequency: 0.00014  dbSNP: rs201004645
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037862 SCV000061524 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000505525 SCV000599757 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-05-09 criteria provided, single submitter clinical testing
Counsyl RCV000505525 SCV000795427 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-11-14 criteria provided, single submitter clinical testing
Mendelics RCV000505525 SCV001138906 benign Autosomal recessive nonsyndromic hearing loss 1A 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002513485 SCV003299681 uncertain significance not provided 2022-04-26 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). This variant is present in population databases (rs201004645, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 11438992, 15603707). ClinVar contains an entry for this variant (Variation ID: 44758). 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 not expected to disrupt GJB2 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037862 SCV003929343 uncertain significance not specified 2023-04-20 criteria provided, single submitter clinical testing Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000505525 SCV001463362 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing

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