Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004789980 | SCV005399104 | pathogenic | COL4A1-related disorder | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease in this gene and is associated with COL4A1-related disorder (MONDO:0800461). Glycine substitutions affecting the Gly-X-Y repeat motif are known to have a dominant-negative mechanism of disease in other collagen genes, but conclusive functional evidence of a dominant-negative mechanism in this gene is not available (PMID: 1867713, 23225343,16159887). (I) 0107 - This gene is associated with autosomal dominant disease. Glycine substitutions in exons 24 and 25 of this gene are associated with angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps (MIM#611773) (PMID: 20301768). (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic carriers of pathogenic variants have been reported in at least one family (PMID: 30413629). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 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 is located in the well-established functional collagen domain and affects a glycine residue in the Gly-X-Y motif (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Gly903Asp) has been observed in multiple unrelated individuals with COL4A1-related symptoms, including two de novo occurrences (DECIPHER, ClinVar, PMID: 32732225, VCGS internal database). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |