Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KRAS : cardiofaciocutaneous syndrome

HGNC:6407 | 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
12
12
Niihori T et al. 2006 Mar (PMID:16474404); Søvik O et al. 2007 Jul (PMID:17601930); Zenker M et al. 2007 Feb (PMID:17056636);
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
1
1
Nava C et al. 2007 Dec (PMID:17704260); Nyström AM et al. 2008 Aug (PMID:18456719); Adachi M et al. 2012 Jan (PMID:21871821);
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
Non-patient cells 0.5 0 - 1 0
Niihori T et al. 2006 Mar (PMID:16474404); Søvik O et al. 2007 Jul (PMID:17601930); Gremer L et al. 2011 Jan (PMID:20949621);
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
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Strong
07/24/2018
REASON(S) FOR CHANGE
See evidence summary
EXPERT CURATION (DATE)
Strong
07/24/2018
EVIDENCE SUMMARY
The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in KRAS patients with CFC (Adachi, Abe, Aoki, & Matsubara, 2012; Nava et al., 2007; Niihori et al., 2006; Nystrom et al., 2008; Sovik et al., 2007; Zenker et al., 2007). However, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of Noonan syndrome versus CFC. Furthermore, there is sufficient variant overlap between KRAS-associated Noonan and CFC phenotypes. Additional genotype:phenotype correlations are necessary to solidify the association of KRAS with CFC syndrome therefore it cannot yet be classified as Definitive. The KRAS gene is also located in the Ras/MAPK pathway which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). In summary, the evidence supporting the KRAS:CFC association is Strong.