Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000991614 | SCV001143222 | likely pathogenic | not provided | 2019-07-30 | criteria provided, single submitter | clinical testing | The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. The best available variant frequency is uninformative because it is below the disease allele frequency. |
| Invitae | RCV000991614 | SCV003322136 | likely pathogenic | not provided | 2023-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1198 of the COL4A3 protein (p.Gly1198Asp). This variant is present in population databases (rs755849032, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 804577). 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 COL4A3 protein function. This variant disrupts the p.Gly1198 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12028435, 15618242, 33226606, 34400539). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Prevention |
RCV003936250 | SCV004757923 | likely pathogenic | COL4A3-related condition | 2023-12-16 | criteria provided, single submitter | clinical testing | The COL4A3 c.3593G>A variant is predicted to result in the amino acid substitution p.Gly1198Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0060% of alleles in individuals of Latino descent in gnomAD. A different nucleotide substitution affecting the same amino acid (p.Gly1198Ser) has been reported in individuals with COL4A3-associated disorders (Longo et al. 2002. PubMed ID: 12028435; Vaisitti et al. 2020. PubMed ID: 33226606; Table S4, Gibson et al. 2021. PubMed ID: 34400539). The p.Gly1198 residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711). Taken together, the c.3593G>A (p.Gly1198Asp) is interpreted as likely pathogenic. |