rs766551411

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001009944.3(PKD1):c.12010C>T(p.Gln4004Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,124 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.79

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-2090802-G-A is Pathogenic according to our data. Variant chr16-2090802-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 434006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090802-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.12010C>T	p.Gln4004Ter	stop_gained	44/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.12010C>T	p.Gln4004Ter	stop_gained	44/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.12007C>T	p.Gln4003Ter	stop_gained	44/46	1		ENSP00000399501	A2	P98161-3
PKD1	ENST00000472577.1 linkuse as main transcript	n.38C>T		non_coding_transcript_exon_variant	1/3	2
PKD1	ENST00000564313.1 linkuse as main transcript	n.531C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000923

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 31, 2017	The PKD1 c.12010C>T; p.Gln4004Ter variant (rs766551411) has been reported in two families with autosomal dominant polycystic kidney disease, and segregating with affected individuals (Audrezet 2012). An immortalized cell line carrying the variant shows reduced PKD1 incorporation in the cellular membrane, and absence in the primary cilia (Herbert 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 434006), and is observed in the general population at a low overall frequency of 0.0004% (1/240348 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Herbert B et al. A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X) in polycystin-1. PLoS One. 2013; 8(1):e55191. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30586318, 23383103, 25525159, 16456780, 22508176, 25333066, 29529603, 31740684, 35325889, 30413633) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Polycystic kidney disease, adult type

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	Jul 19, 2024	PM2_Supporting+PVS1+PS4_Moderate+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been previously reported as pathogenic, and observed in many patients with polycystic kidney disease (PKD) (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and has been observed in patients with PKD (ClinVar, PMID: 29529603, pkdb.mayo.edu) (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	Fulgent Genetics, Fulgent Genetics	May 06, 2022	- -

Polycystic kidney disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Gln4004X variant was identified in 1 of 24 proband chromosomes from a small â€šÃ„Ãºdiscoveryâ€šÃ„Ã¹ cohort in a study developing NGS sequencing of ADPKD genes (Trjillano 2014). The variant was also identified in dbSNP (ID: rs766551411) and ADPKD Mutation Database (definitely pathogenic). The variant was not found in Clinvitae, COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, NHLBI GO, the Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln4004X variant leads to a premature stop codon at position 4004, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Autosomal dominant polycystic kidney disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Jun 05, 2024

- -

PKD1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The PKD1 c.12010C>T variant is predicted to result in premature protein termination (p.Gln4004*). This variant has been reported in individuals with autosomal dominant polycystic kidney disease (ADPKD) (see for example, Trujillano et al. 2014. PubMed ID: 25333066; Xu et al. 2018. PubMed ID: 29529603). This variant is reported in 0.00092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in PKD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.75

MutationTaster

Benign

1.0

A;A

Vest4

0.84

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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