Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ERCC4 : xeroderma pigmentosum group F

HGNC:3436 | MONDO_0010215
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
12
Sijbers AM et al. 1996 Sep 6 (PMID:8797827); Kashiyama K et al. 2013 May 2 (PMID:23623389); Matsumura Y et al. 1998 Jun (PMID:9580660);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
6
Kashiyama K et al. 2013 May 2 (PMID:23623389); Fassihi H et al. 2016 Mar 1 (PMID:26884178); Matsumura Y et al. 1998 Jun (PMID:9580660);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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
Kashiyama K et al. 2013 May 2 (PMID:23623389); Sijbers AM et al. 1998 May (PMID:9579555);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Tian M et al. 2004 Feb (PMID:14729965);
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
08/14/2019
EXPERT CURATION (DATE)
Definitive
08/14/2019
EVIDENCE SUMMARY
There is abundant evidence published associating the ERCC4 gene with xeroderma pigmentosum group F since the gene-disease relationship was first proposed by Sijbers et al. (1996). Multiple case level studies have been performed with XPF patients that have variants in the ERCC4 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. Studies of patient-derived cells showed reduced nucleotide excision repair activity in GG-NER and TC-NER pathways. An XPF deficient mouse model has been established to show consistent phenotypes with XPF patients including growth retardation and DNA repair defects. All of these types of evidence are consistent with a definitive relationship between the ERCC4 gene and xeroderma pigmentosum group F.