Submissions for variant NM_001009944.3(PKD1):c.10698GGCTGT[2] (p.3567AV[2])

dbSNP: rs777460677

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002255	SCV001160131	likely pathogenic	Polycystic kidney disease, adult type	2018-11-24	criteria provided, single submitter	clinical testing	The PKD1 c.10710_10715del; p.Ala3571_Val3572del variant (rs777460677) has been described in the literature in association with autosomal dominant polycystic kidney disease (ADPKD; Alberer 2010, Canaud 2010, He 2018). It is reported in ClinVar (Variation ID: 434001), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes 2 residues (alanine and valine), leaving the rest of the protein in-frame. Based on available information, this variant is considered likely pathogenic. REFERENCES Alberer M et al. Reduced methotrexate clearance and renal impairment in a boy with osteosarcoma and earlier undetected autosomal dominant polycystic kidney disease (ADPKD). J Pediatr Hematol Oncol. 2010 Nov;32(8):e314-6. Canaud G et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am J Transplant. 2010 Jul;10(7):1701-6. He W et al. Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction. BMC Med Genet. 2018 Oct 17;19(1):186.
GeneDx	RCV001837938	SCV002098170	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	In-frame deletion of 2 amino acids in a non-repeat region; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20642692, 20921908, 30333007)
Fulgent Genetics, Fulgent Genetics	RCV001002255	SCV002809353	likely pathogenic	Polycystic kidney disease, adult type	2024-02-15	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001837938	SCV005197986	likely pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499512	SCV000592848	pathogenic	Autosomal dominant polycystic kidney disease		no assertion criteria provided	clinical testing	The p.Ala3571_Val3572del variant was identified by Cannaud (2010) in a kidney donor, whose kidneys were transplanted in two recipients. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a novel hypomorphic mutation in PKD1 (10710_10715del6) as the only likely mutation. This deletion is located in the fourth transmembrane (TM) region of polycystin-1 and is predicted to change the site of the TM domain. The p.Ala3571_Val3572del variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC version 0.3 released January 13, 2015), COSMIC, MutDB, the ClinVar, Clinvitae, GeneInsight COGR through the Canadian Open Genetics Repository (http://opengenetics.ca/) and in LOVD PKD1 and LOVD3.0 PKD1 Databases. The variant was identified in the Mayo Clinic PKD1 database and was classified as Likely Pathogenic. This variant is an in-frame deletion resulting in the removal of Ala residue at codon 3571 and Val residue at codon 3572 resulting in loss a critical domain region and potentially loss of function. This type of variant is expected to cause Autosomal Dominant Polycystic Kidney Disease, consistent with the clinical diagnosis in this individual. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.