Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002272818 | SCV002557214 | uncertain significance | Focal segmental glomerulosclerosis 5 | 2022-02-02 | 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: 0101 - Gain of function is the likely mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, dominant intermediate E (CMT, MIM#614455) and focal segmental glomerulosclerosis 5 (FSGS, MIM#613237). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. In some families with FSGS, carriers of pathogenic variants were clinically unaffected (PMID: 32451589). (I) 0115 - Variants in this gene are known to have variable expressivity. Inter- and intrafamilial variability has been reported, where the same variant was observed in individuals with FSGS, or both FSGS and CMT (PMID: 32451589). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (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 diaphanous inhibitory domain. Many pathogenic variants have been reported in this domain, and functional evidence supports that alteration of this region results in a defective protein (PMID: 32451589). (SP) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. This alternative change (p.Ala203Asp) has been reported as a VUS (ClinVar), and observed in a family with FSGS (PMID: 21866090). (I) 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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Genome Diagnostics Laboratory, |
RCV002294526 | SCV002587405 | uncertain significance | Focal segmental glomerulosclerosis | 2019-12-01 | criteria provided, single submitter | clinical testing |