Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788334 | SCV005399621 | likely pathogenic | Hemolytic uremic syndrome, atypical, susceptibility to, 1 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with basal laminar drusen (MIM#126700), complement factor H deficiency (MIM#609814) and susceptibility to atypical haemolytic uraemic syndrome 1 (aHUS; MIM#235400). (I) 0108 - This gene is associated with both recessive and dominant disease. It is associated with autosomal dominant basal laminar drusen, autosomal recessive and dominant complement factor H deficiency, and is a risk factor for aHUS. There is no clear distinction between missense variants that act in a dominant versus recessive manner, although aHUS is typically autosomal dominant (PMIDs: 24799305, 30930551). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with damaging in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated SCR20 domain (PMIDs: 17973958, 11158219, 25951460). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, two alternative amino acid changes with higher Grantham scores have been classified as pathogenic or likely pathogenic in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in at least five individuals with aHUS (PMIDs: 17973958, 33048203, 28176477, 11158219, 25951460). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed to segregate in two affected members of one family (PMID: 17973958), and also in several asymptomatic members of at least three families with aHUS affected probands (PMIDs: 17973958, 11158219, 25951460). However, two of these asymptomatic family members were shown to have severe haemolysis (PMID: 25951460). This gene is associated with susceptibility to aHUS; nonsegregation is well described for CFH variants (PMIDs: 24799305, 26826462). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Plasma from three individuals from one family with this variant showed severe haemolysis, while two members without the variant showed no appreciable haemolysis. The addition of purified CFH to the variant plasma samples was able to correct this haemolysis (PMID: 25951460). (SP) 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 |