Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV002513485 | SCV005622553 | uncertain significance | not provided | 2025-07-23 | criteria provided, single submitter | clinical testing | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in at least one individual with clinical features associated with non-syndromic hearing loss. Polyphen and MutationTaster predict this amino acid change may be benign. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000037862 | SCV003929343 | uncertain significance | not specified | 2025-12-30 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in GJB2 (autosomal recessive nonsyndromic deafness), allowing no conclusion about variant significance. However, the frequency does exceed the maximum pathogenic allele frequency estimated for autosomal dominant nonsyndromic deafness, suggesting that this variant is unlikely to be causative for that phenotype. c.511G>A has been observed in the heterozygous state in numerous individual(s) affected with autosomal dominant or autosomal recessive Non-Syndromic Hearing Loss, without strong evidence for causality and/or unclear inheritance (example, Wu_2002, Kashef_2015, Davarnia_2012, Bonyadi_2014, Najmabadi_2002, Putcha_2007, Lipan_2011, Nishio_2015, Bazazzadegan_2012, Azaiez_2004, Lin_2001, Chen_2011, Bonyadi_2009, Xiao_2004) but was also observed in the compound heterozygous state in at least 1 individual with autosomal recessive nonsyndromic deafness (Carranza_2016, Carranza_2017). 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. The following publications have been ascertained in the context of this evaluation (PMID: 26346709, 33914963, 25555641, 12172394, 22172221, 24529908, 11968091, 17666888, 15603707, 21287563, 25788563, 22695344, 15365987, 11438992, 21777984, 19715472, 26346709, 36048236, 34652575, 31523594, 30245029, 21868108, 18368581, 20739942, 31569309, 22991996, 31620696, 31834214, 21510145, 32090102, 40493033, 19043807, 28483220, 12172392, 25587757, 25388846, 29501291, 28102197, 27153395, 25447126, 25087612, 17357124, 34581455). ClinVar contains an entry for this variant (Variation ID: 44758). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV002513485 | SCV003299681 | uncertain significance | not provided | 2024-06-26 | 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, 26346709, 34581455). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |
| Mendelics | RCV000505525 | SCV001138906 | benign | Autosomal recessive nonsyndromic hearing loss 1A | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Genomic Diagnostic Laboratory, |
RCV000505525 | SCV000599757 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 1A | 2017-05-09 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular 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. |
| Natera, |
RCV000505525 | SCV001463362 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 1A | 2020-09-16 | no assertion criteria provided | clinical testing | |
| Counsyl | RCV000505525 | SCV000795427 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 1A | 2017-11-14 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |