Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788437 | SCV005400357 | uncertain significance | Atypical hemolytic-uremic syndrome with C3 anomaly | 2024-09-23 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with C3 deficiency, (MIM#613779), hemolytic uraemic syndrome, atypical, susceptibility to, 5, (aHUS; MIM#612925), and macular degeneration, age-related, 9 (AMD; MIM#611378). Missense variants have demonstrated a gain of function mechanism, with loss of function also possible (PMID: 27814381, PMID: 18796626). (I) 0108 - This gene is associated with both recessive and dominant disease. Missense variants with a gain of function mechanism and possible loss of function have been reported in heterozygous individuals with aHUS and/or AMD, whereas heterozygous null variants have been rarely reported in individuals with aHUS (PMID: 18796626; PMID: 29888403). Individuals with biallelic null variants have C3 deficency (PMID: 21501302). (I) 0112 - The condition associated with this gene has incomplete penetrance. Heterozygous individuals with aHUS inherited variants from healthy parents (PMID: 18796626). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated A-macroglobulin TED domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a single heterozygous individual atypical haemolytic uremic syndrome, who had reduced C3 levels and an additional variant in the CFI gene (PMID: 23307876, PMID: 20016463). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant resulted in significantly reduced CFHR1 binding (PMID: 27814381). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |