Gene Validity Curation

TNNT2 - hypertrophic cardiomyopathy

Gene: TNNT2 (HGNC:11949)
Classification - 11/07/2017
Disease: hypertrophic cardiomyopathy (MONDO_0005045)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hypertrophic Cardiomyopathy GCEP GCEP
Evidence Summary:
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.00
0
Proband with predicted or proven null variant 1.5 0-2 10 0.00 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
7.00
7
Thierfelder L et al. 1994 Jun 3 (PMID:8205619); Fujita E et al. 2013 Nov (PMID:23494605); Torricelli F et al. 2003 Dec 1 (PMID:14636924);
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
3.00
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
Thierfelder L et al. 1994 Jun 3 (PMID:8205619);
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
2.00
Walsh R et al. 2017 Feb (PMID:27532257);
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
1.00
1.5
Marques MA et al. 2016 (PMID:27721798);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.50
Anderson PA et al. 1991 Nov (PMID:1934353);
Functional Alteration Patient cells 1 0 - 2 2
1.00
2
Rust EM et al. 1999 May 15 (PMID:10330428);
Non-patient cells 0.5 0 - 1 1.00
Morimoto S et al. 1999 Jul 22 (PMID:10405326); Miller T et al. 2001 Feb 9 (PMID:11060294);
Models Non-human model organism 2 0 - 4 4 2.50 2.5
Tardiff JC et al. 1998 Jun 15 (PMID:9637714); Tardiff JC et al. 1999 Aug (PMID:10449439);
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
(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 6 18 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
04/12/2017
EXPERT CURATION (DATE)
DEFINITIVE
11/07/2017
Approved by the Hypertrophic Cardiomyopathy Gene Curation Working Group