ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.2180T>C (p.Leu727Pro) (rs1616940)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Gharavi Laboratory,Columbia University RCV000681747 SCV000809204 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Athena Diagnostics Inc RCV000681747 SCV000843112 pathogenic not provided 2021-03-03 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 22383692, 21115670, 27835667, 22508176, 24374109). Computational tools predict that this variant is damaging.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000681747 SCV000884348 likely pathogenic not provided 2018-01-21 criteria provided, single submitter clinical testing The PKD1 c.2180T>C; p.Leu727Pro variant (rs1616940) is reported in the literature in 27 unrelated patients with autosomal dominant polycystic kidney disease (Audrezet 2012, Carrera 2016, Cornec-Le Gall 2013, Hoefele 2011, Rossetti 2007, Rosetti 2012, Tan 2014) and is also listed on gene-specific databases (Mayo ADPKD Mutation Database) . This variant is absent from the general population with an average of 126647 alleles reported for this genomic region (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 727 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging. Based on the above information, this variant is considered likely pathogenic. References: Mayo ADPKD Mutation Database: http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?GENE=PKD1&apkd_mode=PROD Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012 Aug;33(8):1239-50. Carrera P et al. Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sci Rep. 2016; 6: 30850. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13. Hoefele J et al. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2011 Jul;26(7):2181-8. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. Tan A et al. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing. J Mol Diagn. 2014 Mar;16(2):216-28.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761328 SCV000891313 likely pathogenic Polycystic kidney disease 3 2018-03-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000681747 SCV000928102 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001095631 SCV001251272 uncertain significance Polycystic kidney disease, adult type 2020-02-05 criteria provided, single submitter research PM2, PP3, PP4, PP5
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV000681747 SCV001422364 likely pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
Molecular Biology Laboratory, Fundació Puigvert RCV001095631 SCV001425170 likely pathogenic Polycystic kidney disease, adult type 2020-02-01 criteria provided, single submitter research
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV001254281 SCV001430247 likely pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV001095631 SCV001752484 pathogenic Polycystic kidney disease, adult type 2021-06-30 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000681747 SCV001762205 likely pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292243 SCV001480597 pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Leu727Pro variant was identified in 19 of 3592 proband chromosomes (frequency: 0.005) from German, French, North American, Spanish, Italian and Japanese individuals or families with ADPKD, and was not identified in 480 control chromosomes from healthy individuals (Hoefele 2011, Audrézet 2012, Rossetti 2012, Hwang 2016, Trujillano 2014, Carrera 2016, Kinoshita 2016). The variant was also identified in dbSNP (ID: rs1616940), ADPKD Mutation Database (classified as Highly Likely Pathogenic), PKD1-LOVD 3.0 (classification by in silico as affecting protein function) and Clinvitae (1X). The variant was not identified in NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (March 14, 2016), the Genome Aggregation Consortium, ClinVar, COGR, MutDB and PKD1-LOVD. The p.Leu727 residue is conserved across mammals and other organisms, and 5 of 5 computational analyses programs (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant is located within a functional domain, the polycystin cation channel, increasing the likelihood that it could have clinical significance. This variant was identified in 2 individuals by our laboratory one young individual with cystic kidney disease and another under the age of 35 with bilateral multicystic kidney disease, hepatic cysts and a family history of ADPKD, increasing the likelihood it may have clinical significance. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.