Submissions for variant NM_001009944.3(PKD1):c.2494dup (p.Arg832fs)

dbSNP: rs1567210630

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Gharavi Laboratory, Columbia University	RCV000681730	SCV000809185	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Molecular Biology Laboratory, Fundació Puigvert	RCV001281197	SCV001425171	pathogenic	Polycystic kidney disease, adult type	2020-02-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV001281197	SCV002018810	pathogenic	Polycystic kidney disease, adult type	2020-03-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000681730	SCV002498924	pathogenic	not provided	2024-09-23	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 (gnomAD); This variant is associated with the following publications: (PMID: 33532864, 22383692, 35778421, 30586318, 31740684)
Fulgent Genetics, Fulgent Genetics	RCV001281197	SCV002800394	pathogenic	Polycystic kidney disease, adult type	2022-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001281197	SCV003934685	pathogenic	Polycystic kidney disease, adult type	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: PKD1 c.2494dupC (p.Arg832ProfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 217134 control chromosomes. c.2494dupC has been reported in the literature in at least three individuals affected with Polycystic Kidney Disease (example, Yu_2022). 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 publication has been ascertained in the context of this evaluation (PMID: 35778421). Five ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, while the other four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000681730	SCV005414331	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
PreventionGenetics, part of Exact Sciences	RCV004740406	SCV005363809	pathogenic	PKD1-related disorder	2024-03-26	no assertion criteria provided	clinical testing	The PKD1 c.2494dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg832Profs*40). This variant was reported to be causative for autosomal dominant polycystic kidney disease (ADPKD) (described as c.2494_2495insC, Rossetti et al. 2012. PubMed ID: 22383692; Table S6A, Kim et al. 2019. PubMed ID: 31740684). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKD1 are expected to be pathogenic. This variant is interpreted as pathogenic.