Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290541 | SCV001478602 | likely pathogenic | X-linked Alport syndrome | 2021-01-21 | criteria provided, single submitter | clinical testing | Variant summary: COL4A5 c.4298G>A (p.Gly1433Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat region (IPR008160) of the encoded protein sequence and is predicted to disrupt the Gly-X-Y repeats in the collagenous domain of the collagen IV alpha 5 chain. Most COL4A5 mutations in patients with Alport syndrome have been reported to reside in the collagenous domain (Hertz, 2009 and HGMD database). This is further corroborated by the existence of a different nucleotide change, c.4298G>T (p.Gly1433Val) that has been observed in a patient with Alport syndrome (HGMD database, and Ma_2011, PMID 21505094). Five of five in-silico tools predict a damaging effect of the variant on protein function. This supports the rationale for this variant as being located in a mutational hot spot and/or a critical and well established functional domain of the COL4A5 gene. This variant also alters the conserved first nucleotide of exon 47 adjacent to the preceding intron 46 splice acceptor site of the COL4A5 gene. Several computational tools predict an impact on normal splicing: One predict the variant abolishes the canonical 3' acceptor site. Two predict the variant weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182609 control chromosomes. To our knowledge, no occurrence of c.4298G>A in individuals affected with Alport Syndrome 1, X-Linked Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Therefore, the impact of this variant on the molecular basis of disease cannot be unequivocally determined. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV001377048 | SCV001574274 | pathogenic | not provided | 2023-10-03 | 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 1433 of the COL4A5 protein (p.Gly1433Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 996230). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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). This variant disrupts the p.Gly1433 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 21505094), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV001290541 | SCV001752462 | likely pathogenic | X-linked Alport syndrome | 2021-06-30 | criteria provided, single submitter | clinical testing |