Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001977546 | SCV002260532 | likely pathogenic | not provided | 2021-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 1238 of the COL4A5 protein (p.Gly1238Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL4A5-related conditions. 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. 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). 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. |
| Fulgent Genetics, |
RCV002497928 | SCV002813818 | likely pathogenic | X-linked Alport syndrome | 2022-01-05 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005238129 | SCV005884916 | uncertain significance | not specified | 2024-12-23 | criteria provided, single submitter | clinical testing | Variant summary: COL4A5 c.3712G>A (p.Gly1238Ser) results in a non-conservative amino acid change within the triple-helical region (UniProt) of the encoded protein sequence. This missense variant disrupts a glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, however, the impact of this specific amino acid change does not allow definitive categorization (PMID: 33854215). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181059 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3712G>A in individuals affected with Alport Syndrome 1, X-Linked Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1473410). Based on the evidence outlined above, the variant was classified as uncertain significance. |