Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001859499 | SCV002317349 | likely pathogenic | not provided | 2023-08-16 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 637 of the COL4A3 protein (p.Gly637Arg). This variant is present in population databases (rs761686437, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive Alport syndrome and/or hematuria (PMID: 34400539; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 266007). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Neuberg Centre For Genomic Medicine, |
RCV000256394 | SCV004176501 | uncertain significance | Autosomal recessive Alport syndrome | 2023-03-01 | criteria provided, single submitter | clinical testing | The missense c.1909G>A (p.Gly637Arg) variant in the COL4A3 gene has been reported previously in compound heterozygous state in patients affected with Alport syndrome (AS) (Petzold, Friederike et al.,2019). This variant is reported with the allele frequency (0.0008%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/Uncertain Significance. The amino acid Glycine at position 637 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Gly637Arg in COL4A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Additional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance. |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000256394 | SCV000323166 | uncertain significance | Autosomal recessive Alport syndrome | no assertion criteria provided | clinical testing | ||
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV001029768 | SCV001192546 | likely pathogenic | Autosomal dominant Alport syndrome | 2019-04-10 | no assertion criteria provided | clinical testing |