Submissions for variant NM_001009944.3(PKD1):c.4346ACA[1] (p.Asn1450del)

dbSNP: rs2092482302

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001577611	SCV001805017	likely pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	Observed in the homozygous state in a fetus with features of a ciliopathy in published literature; the heterozygous parents were found to have clinical features consistent with autosomal dominant polycystic kidney disease (PMID: 32055034); In-frame deletion of 1 amino acid 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: 34645488, 22508176, 32055034)
Athena Diagnostics	RCV001577611	SCV001879431	uncertain significance	not provided	2020-09-22	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001175219	SCV005416382	uncertain significance	Polycystic kidney disease, adult type		criteria provided, single submitter	clinical testing	PM2_Supporting+PM4+PS4_Supporting+PP4
Fulgent Genetics, Fulgent Genetics	RCV001175219	SCV005643264	likely pathogenic	Polycystic kidney disease, adult type	2024-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175219	SCV005885307	likely pathogenic	Polycystic kidney disease, adult type	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.4349_4351delACA (p.Asn1450del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 249718 control chromosomes. c.4349_4351delACA has been reported in the literature in a homozygous fetus and in heterozygous individuals affected with Polycystic Kidney Disease 1 (e.g. Audrezet_2012, Heyer_2016, Kurashige_2014, Shamseldin_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22508176, 26823553, 24611717, 34645488). ClinVar contains an entry for this variant (Variation ID: 917952). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001175219	SCV001338743	likely pathogenic	Polycystic kidney disease, adult type		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001292333	SCV001480637	uncertain significance	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Asn1450del variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, LOVD 3.0, ADPKD Mutation Database, PKD1-LOVD, 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 1450; the impact of this alteration on PKD1 protein function is not known. The same amino acid change caused by a different nucleotide change (PKD1, c.4347_4349del) was identified in the ADPKD Mutation Database, classified as “highly likely pathogenic.” 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.