Submissions for variant NM_001009944.3(PKD1):c.3716ACA[1] (p.Asn1240del)

dbSNP: rs1567202750

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000712616	SCV000843133	likely pathogenic	not provided	2018-06-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000712616	SCV000884343	likely pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001095587	SCV001251221	likely pathogenic	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PM2, PM4, PP4, PP5
GeneDx	RCV000712616	SCV001770015	likely pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency 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: 22508176, 33454723, 12842373)
Fulgent Genetics, Fulgent Genetics	RCV001095587	SCV002810398	likely pathogenic	Polycystic kidney disease, adult type	2021-08-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712616	SCV002822250	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	PKD1: PM2, PS4:Moderate, PM4:Supporting, PP4
PreventionGenetics, part of Exact Sciences	RCV003411652	SCV004107454	pathogenic	PKD1-related disorder	2022-08-19	criteria provided, single submitter	clinical testing	The PKD1 c.3719_3721delACA variant is predicted to result in an in-frame deletion (p.Asn1240del). This variant has been reported in one affected father and his affected son with autosomal dominant polycystic kidney disease (ADPKD) (Rossetti et al. 2003. PubMed ID: 12842373). Of note, we have previously found this variant in the heterozygous state in multiple presumably unrelated patients tested for polycystic kidney disease at PreventionGenetics. In-frame small deletions in the PKD1 gene have been commonly found to be pathogenic for ADPKD (http://pkdb.mayo.edu; Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, we classify this variant as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292332	SCV001480636	likely pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Asn1240del variant was identified in 3 of 1516 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti 2003, Audrezet 2012). The variant was observed to segregate with disease in a father and son diagnosed with the vascular subtype of ADPKD (Rossetti 2003). The variant was also identified in ClinVar (classified as likely pathogenic by Athena Diagnostics), and the ADPKD Mutation Database (classified as highly likely pathogenic).The variant was not identified in dbSNP, LOVD 3.0, or PKD1-LOVD databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of an asparagine (Asn) residue at codon 1240; the impact of this alteration on PKD1 protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.