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

dbSNP: rs1616940

Total submissions: 16

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	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 with or without polycystic liver disease	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 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
GeneDx	RCV000681747	SCV001985347	likely pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26661679, 24374109, 23431072, 22090377, 17582161, 30333007, 25333066, 25646624, 27499327, 22508176, 21115670, 22383692, 29038287, 30816285, 33454723, 33437033, 33532864, 27835667, 30586318, 31027891, 36699011)
Mendelics	RCV001095631	SCV002518864	pathogenic	Polycystic kidney disease, adult type	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001095631	SCV002557248	pathogenic	Polycystic kidney disease, adult type	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic in ClinVar and the Autosomal Dominant Polycystic Kidney Disease (ADPKD) Database (PKDB). It has been reported in multiple individuals with ADPKD in the literature (PMID: 22508176; 24374109). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
New York Genome Center	RCV001095631	SCV005044085	pathogenic	Polycystic kidney disease, adult type	2023-04-28	criteria provided, single submitter	clinical testing	The inherited c.2180T>C p.(Leu727Pro) variant in PKD1 has been reported in the literature in multiple individuals with polycystic kidney disease 1 [PMID: 23431072, 24374109, 29038287, 30333007, 30586318, 31027891, 30816285, 33315352, 33532864, 33437033] and is listed in the Mayo Clinic Polycystic Kidney Disease variant database as Likely Pathogenic [https://pkdb.mayo.edu/variants]. The c.2180T>C variant has been deposited in ClinVar with conflicting interpretations of pathogenicity by multiple submitters, including six Pathogenic and seven Likely Pathogenic entries [ClinVar ID: 562302], and is absent from the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. In silico predictions do not support or refute a damaging effect for p.(Leu727Pro) [CADD score = 24.6, REVEL score = 0.422]. Two other missense variants, p.(Leu727Gln) and p.(Leu727Arg), have also been listed as likely pathogenic in the Mayo Clinic Polycystic Kidney Disease variant database. Based on available evidence, the inherited heterozygous c.2180T>C p.(Leu727Pro) variant identified in PKD1 is classified as Pathogenic.
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000681747	SCV001422364	likely pathogenic	not provided	2019-01-01	flagged submission	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.