Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225152 | SCV002503629 | uncertain significance | Polycystic kidney disease, adult type | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change deletes 15 bp in the splice region of the acceptor site of intron 45 of PKD1. It is absent in a large population cohort (gnomAD v2.1). The nucleotides in the deleted region are moderately to not conserved (100 vertebrates, UCSC), and multiple lines of computational evidence predict an impact on splicing (HSF, MaxEntScan, NNSplice). The predicted effect is loss of the acceptor splice site and activation of a cryptic acceptor site leading to the in-frame retention of 24 bp (excluding the 15 bp deletion) of intron 45, and the insertion of 8 amino acids in the heterotrimeric G-protein binding sequence in the C-terminal cytoplasmic domain (PMID: 20837139). This variant is not reported in relevant medical literature or in the PKD1 mutation database. Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2, PP3. |
| Victorian Clinical Genetics Services, |
RCV002225152 | SCV002557488 | uncertain significance | Polycystic kidney disease, adult type | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (PKD; MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. However, another deletion in the same intron affecting overlapping nucleotides has been reported in a large pedigree with autosomal dominant PKD and was shown to activate a cryptic 3' splice site resulting in a frameshift variant; therefore it was regarded as pathogenic (PMID: 11058904, ADPKD database). (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 |