Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV001843989 | SCV002103269 | likely pathogenic | not provided | 2021-04-02 | criteria provided, single submitter | clinical testing | PS3, PS4_moderate |
| Victorian Clinical Genetics Services, |
RCV004785336 | SCV005399036 | uncertain significance | Hemolytic uremic syndrome, atypical, susceptibility to, 1 | 2024-10-08 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with hemolytic uremic syndrome, atypical, susceptibility to (MIM#235400) and macular degeneration, age-related, reduced risk of (MIM#603075). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (22 heterozygotes, 2 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0603 - Variant is located in the annotated sushi domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Leu290Val) has been observed in a heterozygous individual with atypical haemolytic-uremic syndrome. This variant has also been shown to increase sialic acid binding, competing with FH and impairing complement regulation (PMID: 33651882). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant in cis with p.(Ala296Val) has been reported in multiple individuals with atypical haemolytic-uremic syndrome (aHUS). These two variants result in the c-terminal of the FHR-1 protein converting into the almost identical c-terminal of the FH protein. The p.(Leu290Ser) variant has not been previously reported in an individual with aHUS without being in cis with the p.(Ala296Val) variant (PMID: 28993505). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant on its own has been shown to increase sialic acid binding, competing with FH and impairing complement regulation. The effect was stronger when in cis with the p.(Ala296Val) variant (PMID: 33651882). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |