Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DSPP : dentinogenesis imperfecta (disease)

HGNC:3054 | MONDO_0018849
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hearing Loss
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 1
2
2
Kim JW et al. 2005 Feb (PMID:15592686);
Proband with predicted or proven null variant 1.5 0-2 10 5 7 7
Kim JW et al. 2004 Aug (PMID:15241678); Song YL et al. 2008 Jul (PMID:18456718);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 5
2.5
2.5
Xiao S et al. 2001 Feb (PMID:11175790); Dong J et al. 2005 Jan 30 (PMID:15690376); Zhang X et al. 2007 Aug 8 (PMID:17686168); Kim JW et al. 2005 Feb (PMID:15592686);
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   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.78 3
Xiao S et al. 2001 Feb (PMID:11175790); Dong J et al. 2005 Jan 30 (PMID:15690376);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.78    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Xiao S et al. 2001 Feb (PMID:11175790);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Lee SK et al. 2012 Dec 27 (PMID:23509818);
Models Non-human model organism 2 0 - 4 4 1 2 2
Sreenath T et al. 2003 Jul 4 (PMID:12721295);
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) 3

 


 

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 3 15 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
10/03/2018
EXPERT CURATION (DATE)
Definitive
04/17/2018
EVIDENCE SUMMARY
The DSPP gene has been associated with autosomal dominant dentinogenesis imperfecta using the ClinGen Clinical Validity Framework as of 3/23/17. This association was made using case-level data. At least 8​ variants (missense, frameshift, splice-site) have been reported in humans. DSPP was first associated with this disease in humans as early as 2001 (Xiao et al.​). Association is seen in at least 11 probands in 6 publications (11175790, 15690376, 17686168, 15592686, 18456718, 15241678). Variants in this gene segregated with disease in 52 additional family members. Multiple unrelated families presented with variants at the last position of exon 2 (p.Phe17) or the first position of exon 3 (p.Val18). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, only two families reported by Xiao et al. 2001 had an adult onset progressive high frequency hearing loss, therefore the hearing phenotype was lumped with the dentinogenesis imperfecta syndrome. This gene-disease association is supported by a homozygous DSPP null mouse model with dentinogenesis imperfecta phenotypes, as well as in vitro functional assays. In summary, DSPP is definitively associated with autosomal dominant dentinogenesis imperfecta. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss​ Working Group on 4/17/18.