ClinVar Miner

Submissions for variant NM_005267.5(GJA8):c.262C>A (p.Pro88Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania RCV004593585 SCV005081738 uncertain significance Cataract 1 multiple types 2023-01-21 criteria provided, single submitter curation Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PM1(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:24535056. The cataract phenotype reported for this variant is: Total. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320
Labcorp Genetics (formerly Invitae), Labcorp RCV004593585 SCV005834139 pathogenic Cataract 1 multiple types 2024-08-19 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 88 of the GJA8 protein (p.Pro88Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 24535056). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJA8 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJA8 function (PMID: 24535056). This variant disrupts the p.Pro88 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35531093). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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