Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ERCC2 : xeroderma pigmentosum group D

HGNC:3434 | MONDO_0010212
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer
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
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 3
6
11.5
Frederick GD et al. 1994 Oct (PMID:7849702); Kobayashi T et al. 1997 (PMID:9101292); Broughton BC et al. 2001 Oct 15 (PMID:11709541);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
5.5
Frederick GD et al. 1994 Oct (PMID:7849702); Broughton BC et al. 2001 Oct 15 (PMID:11709541); Falik-Zaccai TC et al. 2012 Aug (PMID:22826098); Takayama K et al. 1995 Dec 1 (PMID:7585650);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.55 1
Falik-Zaccai TC et al. 2012 Aug (PMID:22826098);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.55    
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
2
2
Schubert S et al. 2014 Jul (PMID:24105368);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Falik-Zaccai TC et al. 2012 Aug (PMID:22826098); Keriel A et al. 2002 Apr 5 (PMID:11955452);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Andressoo JO et al. 2006 Aug (PMID:16904611);
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
04/19/2019
EXPERT CURATION (DATE)
Definitive
04/19/2019
EVIDENCE SUMMARY
There is abundant evidence published associating the ERCC2 gene with xeroderma pigmentosum group D since the gene-disease relationship was first proposed by Frederick et al. (1994). Multiple case level studies have been performed with XPD patients that have variants in the ERCC2 gene. 8 complementation groups genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and XP variant (XPV)) in Nucleotide excision repair (NER) pathway were reported to cause Xeroderma Pigmentosum. In cells derived from XPD patients, a reduction of the ligand-dependent transactivation mediated by several nuclear receptors and a deficient global genomic NER were observed as functional alteration in patient cells. Xpd mice exhibit severe photosensitivity, cancer predisposition and segmental progeria which are consistent with patient phenotypes. All of these types of evidence are consistent with a definitive relationship between the ERCC2 gene and xeroderma pigmentosum group D.