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

gnomAD frequency: 0.00001  dbSNP: rs1057518897

Total submissions: 20

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	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 Center for Human Genetics Tuebingen	RCV000518237	SCV001335033	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PKD1: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
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	2024-08-06	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PP1_STR,PS3_MOD,PM2_SUP
GeneDx	RCV000518237	SCV001825814	pathogenic	not provided	2022-11-17	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); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17574468, 27782177, 22333914, 12482949, 32381729, 12842373, 11961010, 25333066, 17582161, 31056860, 27499327, 31740684, 30816285, 16430766, 23431072, 11115377, 22508176, 22383692, 30333007, 26632257, 21694639, 33226606, 33437033, 34032358, 23064367, 33437386, 30586318)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000763371	SCV002499200	pathogenic	Polycystic kidney disease, adult type	2022-01-04	criteria provided, single submitter	clinical testing	PS4, PS3_Moderate, PM2
Molecular Genetics, Royal Melbourne Hospital	RCV001254205	SCV002503644	pathogenic	Autosomal dominant polycystic kidney disease	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change in PKD1 is predicted to replace glutamic acid with lysine at codon 2771, p.(Glu2771Lys). The glutamic acid residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the REJ domain. There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.0003% (3/1,179,636 alleles) in the European (non-Finnish) population, which is consistent with autosomal dominant polycystic kidney disease (ADPKD). This variant has been reported in multiple individuals with a clinical diagnosis of ADPKD, and segregates with disease in multiple families (PMID: 11115377, 23431072, 24694054, 25333066, 26632257, 27499327). The variant has been shown in experimental studies with limited validation to impair the cleavage of Polycystin-1 (PMID: 12482949, 23064367). Computational evidence is uninformative for the missense substitution (REVEL = 0.521). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Strong, PS3_Supporting, PS4.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000763371	SCV002768811	pathogenic	Polycystic kidney disease, adult type	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) (ADPKD). (I) 0107 - This gene is associated with autosomal dominant disease. ADPKD (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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions but very high 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. The variant has previously been reported as pathogenic in multiple families with ADPKD (ClinVar, PMIDs: 11115377, 32381729). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000518237	SCV004026426	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	PM1_SUP, PS4, PM2_SUP, PS3
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000763371	SCV005091037	pathogenic	Polycystic kidney disease, adult type	2023-10-27	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic/Likely Pathogenic by other laboratories (Variation ID 374097). This variant has been previously reported as causative for polycystic kidney disease. (PMID:36646975, 27499327).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763371	SCV005184206	pathogenic	Polycystic kidney disease, adult type	2024-07-19	criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PP1_Strong+PS3
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000763371	SCV005397670	pathogenic	Polycystic kidney disease, adult type	2023-12-15	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 8311 of the coding sequence of the PKD1 gene that results in a glutamic acid to lysine amino acid change at residue 2771 of the polycystin 1, transient receptor potential channel interacting protein. The 2771 residue falls in the REJ domain of PKD1 (UniProt). This is a previously reported variant (ClinVar 374097) that has been observed in many individuals and families affected by polycystic kidney disease (PMID: 36646975, 33437386, 32381729, 33315352, 26632257, 24694054, 27499327, 33532864, 31738409, 32203225, 31056860, 30333007, 25333066, 23431072, 22508176, 17582161, 16430766, 11115377). This variant is present in 1 of 151674 alleles (0.0007%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this glutamic acid to lysine amino acid change would be damaging, and the Glu2771 residue at this position is highly conserved across the vertebrate species examined. Studies suggest that that the protein produced from this variant demonstrates a lack of PC-1 cleavage at the GPS domain (PMID: 23760289, 23064367, 17574468, 12482949). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP1, PP3, PS3, PS4
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	RCV000518237	SCV001422389	likely pathogenic	not provided	2019-01-01	flagged submission	clinical testing
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.