rs1057518897
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001009944.3(PKD1):โc.8311G>Aโ(p.Glu2771Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,609,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (โ โ ).
Frequency
Genomes: ๐ 0.0000066 ( 0 hom., cov: 31)
Exomes ๐: 0.0000027 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 missense
NM_001009944.3 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 7.50
Genes affected
PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in NM_001009944.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
?
Variant 16-2103746-C-T is Pathogenic according to our data. Variant chr16-2103746-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103746-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.8311G>A | p.Glu2771Lys | missense_variant | 23/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.8311G>A | p.Glu2771Lys | missense_variant | 23/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151674Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1458136Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2AN XY: 725372
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 04, 2022 | PS4, PS3_Moderate, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundaciรณ Puigvert | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 13, 2024 | Criteria applied: PS4,PP1_STR,PS3_SUP,PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 27, 2023 | 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). - |
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, flagged submission | clinical testing | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 06, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 25, 2020 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jul 12, 2023 | PM1_SUP, PS4, PM2_SUP, PS3 - |
Autosomal dominant polycystic kidney disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 01, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Polycystic kidney disease Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Hypertensive disorder;C0431718:Multiple renal cysts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 19, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at