Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PKD1 : autosomal dominant polycystic kidney disease

HGNC:9008 | MONDO_0004691
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Harvard/Geisinger Biocuration Core
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 3
4.5
4.5
Reed B et al. 2008 Dec (PMID:18640754); Phakdeekitcharoen B et al. 2000 Oct (PMID:11012875);
Proband with predicted or proven null variant 1.5 0-2 10 5 6.5 6.5
Anonymous et al. 1994 Jun 17 (PMID:8004675); Audrézet MP et al. 2012 Aug (PMID:22508176); Neophytou P et al. 1996 Oct (PMID:8792818);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
0.5
0.5
Audrézet MP et al. 2012 Aug (PMID:22508176);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0.5 0.5  
Candidate gene sequencing 2.11 1
Neophytou P et al. 1996 Oct (PMID:8792818);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.11    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
2
Boletta A et al. 2000 Nov (PMID:11106764);
Protein Interaction 0.5 0 - 2 1 0.5
Tsiokas L et al. 1997 Jun 24 (PMID:9192675);
Expression 0.5 0 - 2 2 1
Chauvet V et al. 2002 Mar (PMID:11891195); Geng L et al. 1996 Dec 15 (PMID:8981910);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Lantinga-van Leeuwen IS et al. 2004 Dec 15 (PMID:15496422); Hopp K et al. 2012 Nov (PMID:23064367);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/31/2019
EXPERT CURATION (DATE)
Definitive
05/22/2019
EVIDENCE SUMMARY
The PKD1 gene has been associated with autosomal dominant polycystic kidney disease in over 12 probands in 5 curated publications. PKD1 was first associated with this disease in humans in 1994 (The European Polycystic Kidney Disease Consortium). Variants in this gene segregate with disease and can occur de novo. The mechanism for disease is known to be loss of function. 125 unique variants (missense, in-frame indel, nonsense, frameshift, large deletion and complex rearrangements) have been classified as Pathogenic in ClinVar, 86 of which are frameshift, nonsense or canonical splice changes. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by ample experimental evidence including expression studies, biochemical function, protein interactions and animal models that recapitulate the human disease. In summary, PKD1 is definitively associated with autosomal dominant polycystic kidney disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Working Group on 5/22/2019 (SOP Version 6).