Submissions for variant NM_001009944.3(PKD1):c.348_352del (p.Asn116fs)

dbSNP: rs2092683596

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001095600	SCV001251236	pathogenic	Polycystic kidney disease, adult type	2020-02-05	criteria provided, single submitter	research	PVS1, PM2
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV001249151	SCV001422414	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001254905	SCV001431012	pathogenic	Polycystic kidney disease	2020-05-28	criteria provided, single submitter	research	PVS1, PM2
GeneDx	RCV001249151	SCV002029010	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17574468, 29529603, 22383692)
Fulgent Genetics, Fulgent Genetics	RCV001095600	SCV002809335	pathogenic	Polycystic kidney disease, adult type	2021-10-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001254905	SCV001480817	pathogenic	Polycystic kidney disease		no assertion criteria provided	clinical testing	The PKD1 p.Asn116LysfsX2 variant was identified in 2 of 566 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, and was not identified in 39 control chromosomes from healthy individuals (Rossetti 2012, Trujillano 2014). The variant was also identified in the ADPKD Mutation Database 2x as definitely pathogenic. The variant was not identified in dbSNP, the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, or PKD1-LOVD 3.0. The c.348_352del variant is predicted to cause a frameshift, which alters the protein amino acid sequence beginning at codon 116 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.