ClinVar Miner

Submissions for variant NM_001009944.3(PKD1):c.8311G>A (p.Glu2771Lys) (rs1057518897)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415041 SCV000492845 pathogenic Multiple renal cysts; Hypertensive disorder 2015-08-19 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000518237 SCV000614545 pathogenic not provided 2020-08-25 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. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant disrupts cleavage of polycystin-1, abolishing its ability to activate downstream signaling (PMID: 12482949). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure
Gharavi Laboratory,Columbia University RCV000518237 SCV000809149 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000763371 SCV000894067 pathogenic Polycystic kidney disease, adult type 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000518237 SCV000927729 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing
Mendelics RCV000763371 SCV001139778 pathogenic Polycystic kidney disease, adult type 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000518237 SCV001335033 pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory,Garvan Institute of Medical Research RCV000518237 SCV001422389 likely pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
Molecular Biology Laboratory, Fundació Puigvert RCV000763371 SCV001425199 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 RCV001254205 SCV001430274 likely pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Institute of Human Genetics, University of Leipzig Medical Center RCV000763371 SCV001441093 pathogenic Polycystic kidney disease, adult type 2019-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000518237 SCV001825814 pathogenic not provided 2021-04-07 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect; the E2771K variant disrupts the normal cleavage of the protein (Qian et al., 2002; Garcia-Gonzalez et al., 2007; Hopp et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33226606, 32381729, 22383692, 21694639, 30816285, 31740684, 31056860, 26632257, 11115377, 16430766, 22508176, 12482949, 22333914, 25333066, 23064367, 12842373, 27782177, 23431072, 30333007, 11961010, 17582161, 17574468, 27499327)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001292353 SCV001480708 likely pathogenic Polycystic kidney disease no assertion criteria provided clinical testing The PKD1 p.Glu2771Lys variant was identified in 33 of 5314 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD and was not identified in 460 control chromosomes from healthy individuals (Audrezet 2012, Carrera 2016, Cornec-Le Gall 2013, Garcia-Gonzalez 2007, Liu 2015, Obeidova 2014, Rossetti 2001, Rossetti 2007, Trujillano 2014, Vouk 2006); several of these studies also demonstrated that the variant segregated with disease (Cornec-Le Gall 2013, Obeidova 2014, Vouk 2006). The variant was also identified in dbSNP (ID: rs1057518897) as "With Pathogenic allele", ClinVar (classified as pathogenic by Athena Diagnostics and two other submitters), and ADPKD Mutation Database (as Highly Likely Pathogenic). The variant was not identified in LOVD 3.0, PKD1-LOVD, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). Two studies demonstrated that the variant disrupts cleavage at the polycystin-1 domain (Garcia-Gonzalez 2007, Paul 2014). The p.Glu2771 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (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 occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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