Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788657 | SCV005399693 | pathogenic | Alport syndrome | 2024-10-09 | 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 Alport syndrome, MONDO:0018965, COL4A3-related. 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) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to asparagine. (I) 0251 - This variant is heterozygous. (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) (1 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. This variant is also located in a splice region; however, in silico predictions for abnormal splicing are conflicting. (SP) 0601 - Variant affects one of the glycine residues of the well-established functional Gly-X-Y motif in the collagen triple helical domain (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Gly230Ser) has been reported as likely pathogenic three times in ClinVar and in an individual with chronic kidney disease and gout (PMID: 36100708). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a compound heterozygous individual with autosomal recessive Alport syndrome (PMID: 24633401) and in a heterozygous individual with glomerulopathy (PMID: 34746741). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |