Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mayo Clinic Laboratories, |
RCV001843966 | SCV002103195 | pathogenic | not provided | 2021-12-09 | criteria provided, single submitter | clinical testing | PM2_supporting, PS4_moderate, PVS1 |
| Victorian Clinical Genetics Services, |
RCV004785335 | SCV005398622 | pathogenic | Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly | 2023-07-17 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with atypical haemolytic uremic syndrome 2 (aHUS) (MIM#612922). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in aHUS are predominantly heterozygous, however rare reports of biallelic inheritance have been associated an earlier onset and more severe symptoms (ClinVar, OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic heterozygotes are commonly reported, with penetrance estimated to be 50% (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least ten other variants predicted to result in a loss of function have previously been reported in individuals with aHUS (ClinVar, DECIPHER). (SP) 0808 - Previous evidence of pathogenicity for this variant is conflicting. The variant has previously been observed in combination with other variants in one individual with aHUS (PMID: 28461395); and classified as pathogenic by a diagnostic laboratory in ClinVar. (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) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |