Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
UNC Molecular Genetics Laboratory, |
RCV001195700 | SCV001366104 | likely pathogenic | Alport syndrome | 2020-02-20 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001863094 | SCV002204891 | pathogenic | not provided | 2021-06-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly230 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 30968591, 8940267, 19728970), which suggests that this may be a clinically significant amino acid residue. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 930192). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 230 of the COL4A5 protein (p.Gly230Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. |