Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV000021659 | SCV001427132 | pathogenic | X-linked Alport syndrome | 2018-07-18 | criteria provided, single submitter | clinical testing | A hemizygous missense variant, NM_000495.4(COL4A5):c.4913G>A, has been identified in exon 50 of 51 of the COL4A5 gene. The variant is predicted to result in a major amino acid change from cysteine to tyrosine at position 1638 of the protein (NP_000486.1(COL4A5):p.(Cys1638Tyr)). The cysteine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G), but has been previously described as pathogenic in a family with Alport syndrome (Wilson, J. C. et al. (2007)). In addition, functional analysis of p.(Cys1638Tyr) showed a significant reduction in collagen protein assembly and secretion (Kobayashi, T. and Uchiyama, M. (2010)). A different variant in the same codon resulting in a change to serine has also been reported in a patient with Alport syndrome (Weber, S. et al. (2016)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. |
| Invitae | RCV001389981 | SCV001591546 | pathogenic | not provided | 2021-12-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 20130921). 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: 24780). This missense change has been observed in individual(s) with Alport syndrome (PMID: 17277342). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1638 of the COL4A5 protein (p.Cys1638Tyr). |