rs1057518897

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001009944.3(PKD1):c.8311G>A(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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 7.50

Variant links:

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]

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

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 rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8311G>A	p.Glu2771Lys	missense_variant	Exon 23 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.8311G>A	p.Glu2771Lys	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458136

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725372

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151674

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74022

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Pathogenic:10

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 19, 2024

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP1_Strong+PS3 -

Feb 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.8311G>A (p.Glu2771Lys) results in a conservative amino acid change located in the REJ domain (IPR014010) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246760 control chromosomes. c.8311G>A has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease, and the variant was shown to segregate with disesase in at least one family (e.g., Rossetti_2001, Munch_2020). At least two publications report experimental evidence evaluating an impact on protein function (e.g., Qian_2002, Garcia-Gonzalez_2007). The most pronounced variant effect results in inhibitition of cleavage at the GPS domain, which is important for the normal function of polycystin-1 . ClinVar contains an entry for this variant (Variation ID: 374097). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Jan 04, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PS3_Moderate, PM2 -

Aug 06, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PP1_STR,PS3_MOD,PM2_SUP -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

not provided

Pathogenic:7

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting -

Aug 25, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 -

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Jul 12, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1_SUP, PS4, PM2_SUP, PS3 -

Nov 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 06, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant polycystic kidney disease

Pathogenic:2

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 v4.1 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 v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Strong, PS3_Supporting, PS4. -

Polycystic kidney disease

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Hypertensive disorder;C0431718:Multiple renal cysts

Pathogenic:1

Aug 19, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.011

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.81

Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);

MVP

0.89

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.45

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over