Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Mendelian Genomics, |
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, |
RCV000518237 | SCV000809149 | pathogenic | not provided | 2018-09-16 | criteria provided, single submitter | research | |
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 | |
Ce |
RCV000518237 | SCV001335033 | pathogenic | not provided | 2020-05-01 | criteria provided, single submitter | clinical testing | |
Molecular Biology Laboratory, |
RCV000763371 | SCV001425199 | likely pathogenic | Polycystic kidney disease, adult type | 2020-02-01 | criteria provided, single submitter | research | |
Molecular Genetics of Inherited Kidney Disorders Laboratory, |
RCV001254205 | SCV001430274 | likely pathogenic | Autosomal dominant polycystic kidney disease | 2019-01-01 | criteria provided, single submitter | research | |
Institute of Human Genetics, |
RCV000763371 | SCV001441093 | pathogenic | Polycystic kidney disease, adult type | 2019-01-01 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000763371 | SCV002499200 | pathogenic | Polycystic kidney disease, adult type | 2022-01-04 | criteria provided, single submitter | clinical testing | PS4, PS3_Moderate, PM2 |
Molecular Genetics, |
RCV000763371 | SCV002503644 | pathogenic | Polycystic kidney disease, adult type | 2022-04-22 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glutamic acid with lysine at codon 2771 of the PKD1 protein, p.(Glu2771Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the REJ domain. There is a small physicochemical difference between glutamic acid and lysine. The variant is present in a single individual in a large population cohort (PM2; rs1057518897, 1/142,922 alleles in gnomAD v3.0). The variant has been reported in at least 15 autosomal dominant polycystic kidney disease (ADPKD) probands (PS4; PMID: 11115377, 23431072, 24694054, 25333066, 26632257, 27499327). Segregation of the variant with disease has been demonstrated in at least 4 families (PP1_Strong; PMID: 23431072, 24694054). The variant has been shown in experimental studies to impair the cleavage of Polycystin-1 (PS3_Supporting; PMID: 12482949, 23064367). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PS4, PP1_Strong, PM2, PS3_Supporting, PP3. |
Victorian Clinical Genetics Services, |
RCV000763371 | SCV002768811 | 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) (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 (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions but very high conservation. (I) 0600 - Variant is located in the annotated REJ domain (PDB). (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, HGMD, PMIDs: 11115377, 32381729). (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 |
Institute for Clinical Genetics, |
RCV000518237 | SCV004026426 | pathogenic | not provided | 2023-07-12 | criteria provided, single submitter | clinical testing | PM1_SUP, PS4, PM2_SUP, PS3 |
Molecular Genetics of Inherited Kidney Disorders Laboratory, |
RCV000518237 | SCV001422389 | likely pathogenic | not provided | 2019-01-01 | flagged submission | clinical testing | |
Department of Pathology and Laboratory Medicine, |
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. |