Gene Validity Classification Summary

Gene/Disease Pair:

PTCH1 : nevoid basal cell carcinoma syndrome

HGNC:9585 | MONDO_0007187
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
4
4
Johnson RL et al. 1996 Jun 14 (PMID:8658145); Hahn H et al. 1996 Jun 14 (PMID:8681379);
Proband with predicted or proven null variant 1.5 0-2 10 9 9
Hahn H et al. 1996 Jun 14 (PMID:8681379); Fujii K et al. 2003 Aug 15 (PMID:12900905);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.25
0.25
Johnson RL et al. 1996 Jun 14 (PMID:8658145);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
1
1
Fan Z et al. 2008 May (PMID:18285427); Pastorino L et al. 2009 Jul (PMID:19533801);
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 5 4
Goodrich LV et al. 1997 Aug 22 (PMID:9262482); Ohba S et al. 2008 May (PMID:18477452); Black GC et al. 2003 Dec 15 (PMID:14570707); Aszterbaum M et al. 1999 Nov (PMID:10545995);
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) 5

 


 

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 5 17 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
EXPERT CURATION (DATE)
Definitive
06/04/2018
EVIDENCE SUMMARY
There has been sufficient amount of evidence published associating the PTCH1 gene with nevoid basal cell carcinoma syndrome (Gorlin syndrome) since the gene-disease relationship was first proposed by Johnson et al. (1996). Plenty of case level studies have been performed with BCC patients that have variants in the PTCH1 gene. Multiple PTCH1 deficient mouse models have been established to show consistent phenotypes with NBCCS patients. Untreated Ptch+/– mice have microscopic skin tumors. UV and ionizing radiation enhances BCC tumorigenesis in Ptch+/– mouse. All of these types of evidence suggest a definitive relationship between the PTCH1 gene and nevoid basal cell carcinoma syndrome (Gorlin syndrome).