Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV002252213 | SCV002523833 | uncertain significance | See cases | 2020-11-02 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS4, PM2, PP3 |
| Labcorp Genetics |
RCV000681698 | SCV003524985 | likely pathogenic | not provided | 2022-06-25 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1198 of the COL4A3 protein (p.Gly1198Ser). This missense change has been observed in individuals with COL4A3-related conditions (PMID: 12028435, 15618242, 33226606, 34400539). ClinVar contains an entry for this variant (Variation ID: 562260). 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. 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. |
| Victorian Clinical Genetics Services, |
RCV004788108 | SCV005398637 | pathogenic | Alport syndrome | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss-of-function are known mechanisms of disease in this gene and are associated with COL4A3-related nephropathy. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial hematuria MIM#141200) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant affects a glycine within the well-established functional G-X-Y repeat of a triple helical region (Uniprot). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A different variant in the same codon resulting in a change to an aspartic acid has been reported as likely pathogenic (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in two patients with autosomal dominant Alport syndrome (PMID: 12028435, 15618242) and also once as pathogenic in LOVD. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Gharavi Laboratory, |
RCV000681698 | SCV000809148 | likely pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research |