Gene Validity Classification Summary

Gene/Disease Pair:

EXT1 : exostoses, multiple, type 1

HGNC:3512 | MONDO_0007585
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
3
3
Philippe C et al. 1997 Sep (PMID:9326317);
Proband with predicted or proven null variant 1.5 0-2 10 12 10
Ahn J et al. 1995 Oct (PMID:7550340); Hecht JT et al. 1997 Jan (PMID:8981950); Philippe C et al. 1997 Sep (PMID:9326317);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1
1
Hecht JT et al. 1997 Jan (PMID:8981950); Philippe C et al. 1997 Sep (PMID:9326317);
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
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
Philippe C et al. 1997 Sep (PMID:9326317); Duncan G et al. 2001 Aug (PMID:11518722);
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
Matsumoto K et al. 2010 Jun 15 (PMID:20534475); Sinha S et al. 2017 Apr (PMID:28445472); Zak BM et al. 2011 May 1 (PMID:21310272);
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
05/29/2018
EXPERT CURATION (DATE)
Definitive
06/04/2018
EVIDENCE SUMMARY
There has been sufficient amount of evidence published associating the EXT1 gene with Hereditary Multiple Exostoses (HME) since the gene-disease relationship was first proposed by Ahn et al. (1995). Plenty of case level studies have been performed with HME patients that have variants in the EXT1 gene. EXT2 also cause hereditary multiple exostoses and a working model for the formation of exostoses has been proposed to link the heparan sulfate biosynthesis function of EXT1. Multiple mouse models have been established to show the development of osteochondromas and exostoses with EXT1 deficiency. All of these evidence suggest a definitive relationship between the EXT1 gene and Hereditary Multiple Exostoses (HME).