Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

POLH : xeroderma pigmentosum variant type

HGNC:9181 | MONDO_0010214
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 9
Masutani C et al. 1999 Jun 17 (PMID:10385124); Johnson RE et al. 1999 Jul 9 (PMID:10398605);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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
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
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Lin Q et al. 2006 Jan 1 (PMID:16397220); Ohkumo T et al. 2006 Oct (PMID:17015482);
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 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
There is abundant evidence published associating the POLH gene with xeroderma pigmentosum variant type since the gene-disease relationship was first proposed by Masutani et al. (1999). Multiple case level studies have been performed with XPV patients that have variants in the POLH 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. Multiple Polh deficient mouse models have been established to show consistent phenotypes with XPV patients, including highly susceptible to ultraviolet-induced carcinogenesis and the formation of epithelial and mesenchymal tumors. All of these types of evidence are consistent with a definitive relationship between the POLH gene and xeroderma pigmentosum variant type.