Gene Validity Classification Summary

Gene/Disease Pair:

ERCC3 : xeroderma pigmentosum group B

HGNC:3435 | MONDO_0012531
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer EP
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 5
Weeda G et al. 1990 Aug 24 (PMID:2167179); Oh KS et al. 2006 Nov (PMID:16947863);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
Fassihi H et al. 2016 Mar 1 (PMID:26884178);
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) 11
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
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 1
Oh KS et al. 2006 Nov (PMID:16947863);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Andressoo JO et al. 2009 Mar (PMID:19114557);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 11 6 17 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
There is abundant evidence published associating the ERCC3 gene with xeroderma pigmentosum group B since the gene-disease relationship was first proposed by Weeda et al. (1990). Multiple case level studies have been performed with XPB patients that have variants in the ERCC3 gene. Although germline ERCC3 variants are rare, eight known disease-causing mutations from six patients have been reported to date. 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 decreased DNA repair rates and decreased levels of XPB protein. An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome has been established to show consistent phenotypes with XPB patients by recapitulating the UV sensitivity. All of these types of evidence are consistent with a definitive relationship between the ERCC3 gene and xeroderma pigmentosum group B.