Submissions for variant NM_001009944.3(PKD1):c.4825ATC[1] (p.Ile1610del)

dbSNP: rs1567198691

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249170	SCV001422375	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535841	SCV001752448	likely pathogenic	Polycystic kidney disease, adult type	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001249170	SCV001875059	likely pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Not observed at a 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: 33437033, 35325889, 22383692)
(GEEPAD) Grupo de Estudio de la Enfermedad Poliquística Autosómica Dominante, Hospitales Universitarios Virgen de las Nieves y San Cecilio (Granada)	RCV001535841	SCV002558719	likely pathogenic	Polycystic kidney disease, adult type	2022-08-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001535841	SCV002767400	uncertain significance	Polycystic kidney disease, adult type	2021-05-06	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: 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) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated PKD 11 domain (Uniprot). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic in individuals with polycystic kidney disease (PMID: 22383692, 27499327). However, the most recent reports have classified it as VUS (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001535841	SCV005420450	likely pathogenic	Polycystic kidney disease, adult type	2024-10-04	criteria provided, single submitter	research	PS4,PM2,PM4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292406	SCV001480809	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Ile1610del variant was identified in 1 of 460 proband chromosomes (frequency: 0.0022) from individuals or families with PKD and was classified in this study as “likely pathogenic (Rossetti 2012). The variant was also identified in ADPKD Mutation Database (9x as likely pathogenic). The variant was not identified in ClinVar, LOVD 3.0, or PKD1-LOVD. The variant was identified in control databases in 2 of 276082 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34414 chromosomes (freq: 0.000029), European (Non-Finnish) in 1 of 125782 chromosomes (freq: 0.000008); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. This variant is an in-frame deletion resulting in the removal of an isoleucine (Ile) residue at codon 1610; 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. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003416123	SCV004114502	pathogenic	PKD1-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The PKD1 c.4828_4830delATC variant is predicted to result in an in-frame deletion (p.Ile1610del). This variant has been reported in individuals with autosomal dominant polycystic kidney disease (ADPKD) (Rossetti et al. 2012. PubMed ID: 22383692; Table S3 of Bleyer et al. 2022. PubMed ID: 35325889; Table S3 of Mallawaarachchi et al. 2021. PubMed ID: 33437033). In addition, at PreventionGenetics, we have also detected this variant in multiple presumably unrelated patients tested for polycystic kidney disease. Of note, in-frame small deletions in the PKD1 gene have been commonly reported to be pathogenic for ADPKD (http://pkdb.mayo.edu). This variant is reported in 0.004% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.