Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| SIB Swiss Institute of Bioinformatics | RCV002246206 | SCV002515921 | pathogenic | Cataract 1 multiple types | 2022-05-20 | criteria provided, single submitter | curation | This variant is interpreted as pathogenic for Cataract 1, multiple types, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 upgraded to strong); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5); Located in a mutational hot spot and/or critical and well-established functional domain (PM1). |
| Invitae | RCV002246206 | SCV003238191 | pathogenic | Cataract 1 multiple types | 2022-10-08 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 35531093). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1684590). 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 expected to disrupt GJA8 protein function. Experimental studies have shown that this missense change affects GJA8 function (PMID: 35531093). 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: 9497259, 10362609, 12800976, 19073179). 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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the GJA8 protein (p.Pro88Leu). This variant is not present in population databases (gnomAD no frequency). |
| Revvity Omics, |
RCV002246206 | SCV003816807 | uncertain significance | Cataract 1 multiple types | 2019-03-19 | criteria provided, single submitter | clinical testing | |
| Dept. |
RCV002246206 | SCV005081740 | likely pathogenic | 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: PP1(Strong), PM1(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:35531093. The cataract phenotype reported for this variant is: Variable: total/nuclear/zonular. Additional phenotype/s reported in these individual/s are: Secondary nystagmus or strabismus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 |