Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MAP2K2 : cardiofaciocutaneous syndrome

HGNC:6842 | MONDO_0015280
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: RASopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
14
12
Rodriguez-Viciana P et al. 2006 Mar 3 (PMID:16439621); Narumi Y et al. 2007 Apr 15 (PMID:17366577); Nava C et al. 2007 Dec (PMID:17704260); Nyström AM et al. 2008 Aug (PMID:18456719);
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
0.5
0.5
Narumi Y et al. 2007 Apr 15 (PMID:17366577); Nyström AM et al. 2008 Aug (PMID:18456719); Karaer K et al. 2015 Feb (PMID:25487361);
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
 
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
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2 0.5
Rauen KA et al. 2013 July 15 (PMID:23875798);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0
0
Terao M et al. 2010 Oct (PMID:20518782);
Non-patient cells 0.5 0 - 1 0
Rodriguez-Viciana P et al. 2006 Mar 3 (PMID:16439621); Senawong T et al. 2008 Feb 1 (PMID:17981815); Rodriguez-Viciana P et al. 2008 (PMID:18413255);
Models Non-human model organism 2 0 - 4 4
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) 0.5

 


 

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 0.5 12.5 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
07/24/2018
EXPERT CURATION (DATE)
Definitive
07/24/2018
EVIDENCE SUMMARY
There is a definitive association between alteration of the MAP2K2 gene and CFC syndrome. The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in MAP2K2 in patients with CFC (Narumi et al., 2007; Nava et al., 2007; Nystrom et al., 2008; Rodriguez-Viciana, Tetsu, et al., 2006). The MAP2K2 gene is also located in the Ras/MAPK pathway which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013).