Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001997681 | SCV002239320 | uncertain significance | not provided | 2021-03-25 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with COL4A3-related conditions. 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. 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 is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 815 of the COL4A3 protein (p.Gly815Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. |
| Prevention |
RCV004744183 | SCV005359551 | likely pathogenic | COL4A3-related disorder | 2024-04-15 | no assertion criteria provided | clinical testing | The COL4A3 c.2444G>A variant is predicted to result in the amino acid substitution p.Gly815Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant occurs at the conserved triple helical domain (residues 43-1438) of the COL4A3 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). At the glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with a glutamic acid (Glu) have been widely reported to be pathogenic or likely pathogenic for autosomal dominant or recessive COL4A3 nephropathy (see for example, p.Gly207Glu Gao et al. 2022. PubMed ID: 36685964, autosomal dominant; p.Gly233Glu in Supplementary Table 2 of Sen et al. 2017. PubMed ID: 28780565, autosomal dominant; p.Gly499Glu in Zhang et al. 2021. PubMed ID: 33772369, autosomal recessive; p.Gly1015Glu in Badenas et al. 2002. PubMed ID: 11961012, autosomal dominant). Therefore, the c.2444G>A (p.Gly815Glu) variant is interpreted as likely pathogenic for both autosomal dominant and recessive COL4A3 nephropathy. |