Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute Of Human Genetics Munich, |
RCV000995727 | SCV001150052 | likely pathogenic | Autosomal recessive Alport syndrome | 2018-03-16 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000786944 | SCV001427162 | pathogenic | Autosomal dominant Alport syndrome | 2018-11-21 | criteria provided, single submitter | clinical testing | A heterozygous missense variant, NM_000091.4(COL4A3):c.1594G>T, has been identified in exon 25 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from glycine to cysteine at position 532 of the protein (NP_000082.2(COL4A3):p.(Gly532Cys)). The glycine at this position has very high conservation (100 vertebrates, UCSC), and is located within the triple helix essential 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). However, heterozygotes of three different variants in the same codon resulting in a change to serine (0.0008%), arginine (0.0004%) and aspartic acid (0.0008%) have been found in the population. The variant has been previously described as pathogenic and segregated with disease in at least one family with hematuria (Wang, Y.Y. et al., 2004). In addition, p.(Gly532Cys) has been reported heterozygous in an Alport Syndrome patient (Weber, S. et al., 2016). A different variant in the same codon resulting in a change to aspartic acid has also been shown to cause autosomal recessive Alport syndrome (Nagel, M. et al. 2005). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. |
| Invitae | RCV001856210 | SCV002238418 | pathogenic | not provided | 2022-04-29 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 532 of the COL4A3 protein (p.Gly532Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Alport syndrome (PMID: 14871398, 26809805, 31387071). ClinVar contains an entry for this variant (Variation ID: 635483). 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. For these reasons, this variant has been classified as Pathogenic. |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000786944 | SCV000925848 | pathogenic | Autosomal dominant Alport syndrome | 2019-02-08 | no assertion criteria provided | clinical testing |