Gene Validity Classification Summary

Gene/Disease Pair:

MYL2 : Hypertrophic Cardiomyopathy

HGNC:7583 | OrphaNet: 217569 | OMIM:608758
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

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
0.0
0
Proband with predicted or proven null variant 1.5 0-2 10 0.0 0
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 11.5 7
Berge KE et al. 2014 Oct (PMID:24111713); Flavigny J et al. 1998 Mar (PMID:9535554); Kabaeva ZT et al. 2002 Nov (PMID:12404107); Mörner S et al. 2003 Jul (PMID:12818575); Richard P et al. 2003 May 6 (PMID:12707239); Lopes LR et al. 2015 Feb (PMID:25351510); Poetter K et al. 1996 May (PMID:8673105); Garcia-Pavia P et al. 2011 Nov (PMID:21896538); Claes GR et al. 2016 Jun 14 (PMID:26497160);
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 LOD Score Examples 3 5 0-7 7 0.5 0.5
Flavigny J et al. 1998 Mar (PMID:9535554);
2 4
1.5 3
1 1.5
   
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 12 2.0 2
Walsh R et al. 2017 Feb (PMID:27532257);
Total Genetic Evidence Points (Maximum 12) 9.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 2.0 2
Szczesna D et al. 2001 Mar 9 (PMID:11102452); Price KM et al. 1980 Nov 1 (PMID:7236212); Rayment I et al. 1993 Jul 2 (PMID:8316857);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 0.0 0
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 4.0 4
Wang Y et al. 2006 Aug 11 (PMID:16837010); Szczesna-Cordary D et al. 2005 Aug 15 (PMID:16076902); Kerrick WG et al. 2009 Mar (PMID:18987303); Zhou Z et al. 2016 (PMID:27378946); Grey C et al. 2005 May 15 (PMID:15829506);
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 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 9.5 6 15.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
02/07/2017
EXPERT CURATION (DATE)
DEFINITIVE
02/07/2017
Approved by the Hypertrophic Cardiomyopathy Gene Curation Working Group