Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001286160 | SCV001472689 | uncertain significance | Polycystic kidney disease, adult type | 2019-11-02 | criteria provided, single submitter | clinical testing | The PKD1 c.359+5G>A variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a well conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Other variants altering this splice site (c.359+1G>A, c.359+2T>C, c.359+2T>G) have been reported in individuals affected with ADPKD (Audrezet 2012, Irazabal 2011, Kinoshita 2016). However, given the lack of clinical and functional data, the significance of the c.359+5G>A variant is uncertain at this time. REFERENCES Audrezet MP et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012 Aug;33(8):1239-50. Irazabal MV et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011 Jun;6(6):1274-85. Kinoshita M et al. Technical Evaluation: Identification of Pathogenic Mutations in PKD1 and PKD2 in Patients with Autosomal Dominant Polycystic Kidney Disease by Next-Generation Sequencing and Use of a Comprehensive New Classification System. PLoS One. 2016 Nov 11;11(11):e0166288. |
| Fulgent Genetics, |
RCV001286160 | SCV002805597 | uncertain significance | Polycystic kidney disease, adult type | 2022-02-15 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV001286160 | SCV005087081 | likely pathogenic | Polycystic kidney disease, adult type | 2024-10-08 | 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 polycystic kidney disease 1 (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 (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been classified as a VUS by diagnostic laboratories 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) 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 |