Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PLN : Intrinsic Cardiomyopathy

MONDO:0000591 | ORPHA:167848 | OMIM:115196
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
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
Minamisawa S et al. 2003 Apr 25 (PMID:12705874); Haghighi K et al. 2003 Mar (PMID:12639993); Chiu C et al. 2007 Sep (PMID:17655857); Landstrom AP et al. 2011 Jan (PMID:21167350); DeWitt MM et al. 2006 Oct 3 (PMID:17010801); van der Zwaag PA et al. 2012 Nov (PMID:22820313); Schmitt JP et al. 2003 Feb 28 (PMID:12610310); Medeiros A et al. 2011 Dec (PMID:22137083);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Haghighi K et al. 2003 Mar (PMID:12639993);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
0.50
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
1.50
1.5  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
Haghighi K et al. 2003 Mar (PMID:12639993);
3-4.99 1 2
Haghighi K et al. 2006 Jan 31 (PMID:16432188);
≥5 1.5 3
Schmitt JP et al. 2003 Feb 28 (PMID:12610310);
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
1.50
Walsh R et al. 2017 Feb (PMID:27532257);
Total Genetic Evidence Points (Maximum 12) 10.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2
0.50
2
Toyofuku T et al. 1993 Feb 5 (PMID:8428955);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1.50
McTiernan CF et al. 1999 Mar (PMID:10198197); Meyer M et al. 1995 Aug 15 (PMID:7641356);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 0.50
Haghighi K et al. 2003 Mar (PMID:12639993);
Models Non-human model organism 2 0 - 4 4 5.00 4
Dash R et al. 2001 Feb 13 (PMID:11171800); Kadambi VJ et al. 1996 Jan 15 (PMID:8567978); Luo W et al. 1994 Sep (PMID:8062415); Luo W et al. 1998 Feb 20 (PMID:9468536); Pattison JS et al. 2008 Apr (PMID:17882530); Haghighi K et al. 2006 Jan 31 (PMID:16432188); Haghighi K et al. 2006 Jan 31 (PMID:16432188); (Only two non-human model organism were awarded points PMIDs: 16432188 and 11171800. The others did not obtain a score due to insufficient evidence or phenotyping.)
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 10.5 6 16.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
08/29/2017
EXPERT CURATION (DATE)
DEFINITIVE
09/19/2017
Approved by the Hypertrophic cardiomyopathy Gene Curation Expert Panel