Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001855318 | SCV002240949 | pathogenic | not provided | 2021-08-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). 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 COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 522413). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 28844315; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 896 of the COL4A5 protein (p.Gly896Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. |
Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000625549 | SCV000746044 | likely pathogenic | X-linked Alport syndrome | 2017-09-18 | no assertion criteria provided | clinical testing | |
Sydney Genome Diagnostics, |
RCV001328293 | SCV001449278 | pathogenic | Alport syndrome | 2018-10-24 | no assertion criteria provided | clinical testing | This patient is hemizygous for the c.2686G>A p.(Gly896Ser) variant in exon 32 of the COL4A5 gene. To our knowledge, this variant has not been previously reported. This variant results in substitution of one of the invariant glycine residues in the triple helical domain of type I collagen, and is considered to be pathogenic. |