Gene Validity Classification Summary

Gene/Disease Pair:

PRKAG2 : Hypertrophic cardiomyopathy

MONDO:0010946 | ORPHA:217569 | OMIM:600858
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

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
2.00
2
Liu Y et al. 2013 (PMID:23741347);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
5.70
5.7
Blair E et al. 2001 May 15 (PMID:11371514); Arad M et al. 2002 Feb (PMID:11827995); Kelly BP et al. 2009 Nov (PMID:19787389); Laforêt P et al. 2006 Mar (PMID:16487706); Morita H et al. 2008 May 1 (PMID:18403758); Arad M et al. 2005 Jan 27 (PMID:15673802);
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
MacRae CA et al. 1995 Sep (PMID:7657794); Arad M et al. 2002 Feb (PMID:11827995);
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
1.50
2
Hinson JT et al. 2016 Dec 20 (PMID:28009297); Banerjee SK et al. 2010 Feb (PMID:20005292);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.50
Lang T et al. 2000 Dec 1 (PMID:11112354);
Functional Alteration Patient cells 1 0 - 2 2
1.00
1
Hinson JT et al. 2016 Dec 20 (PMID:28009297);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3.00 3
Arad M et al. 2003 Jun 10 (PMID:12782567); Sidhu JS et al. 2005 Jan 4 (PMID:15611370); Davies JK et al. 2006 May (PMID:16339829);
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
01/30/2017
EXPERT CURATION (DATE)
DEFINITIVE
04/04/2017
Approved by the Hypertrophic Cardiomyopathy Gene Curation Working Group