Gene Validity Classification Summary

Gene/Disease Pair:

PTPN11 : Noonan syndrome with multiple lentigines

HGNC:9644 | MONDO_0007893
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: RASopathy EP
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
8
8
Sarkozy A et al. 2004 May (PMID:15121796); Motegi S et al. 2015 Nov (PMID:25917897);
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
5
Digilio MC et al. 2002 Aug (PMID:12058348); Maridet C et al. 2016 Jun (PMID:26952712); Lin IS et al. 2009 Oct (PMID:19864201); Sarkozy A et al. 2004 May (PMID:15121796); Kim J et al. 2011 May (PMID:21747628); Motegi S et al. 2015 Nov (PMID:25917897);
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
1
1.5
Edouard T et al. 2010 May (PMID:20308328);
Non-patient cells 0.5 0 - 1 0.5
Hanna N et al. 2006 May 1 (PMID:16638574);
Models Non-human model organism 2 0 - 4 4 1 1
Marin TM et al. 2011 Mar (PMID:21339643); Stewart RA et al. 2010 May 18 (PMID:20493809);
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) 3

 


 

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 3 15 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
07/25/2018
EXPERT CURATION (DATE)
Definitive
07/25/2018
EVIDENCE SUMMARY
There is a definitive association between alteration of the PTPN11 gene and the NSML phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in PTPN11 in patients with NSML (Digilio et al., 2002; Kim, Kim, Kim, Lee, & Lee, 2011; Lin, Wang, Chao, Wu, & Lin, 2009; Maridet et al., 2016; Motegi et al., 2015; Sarkozy, 2004). Additionally, the mechanism of disease has been characterized as LOF compared to that of PTPN11-NS which is GOF (Edouard et al., 2010; Hanna et al., 2006; Marin et al., 2011; Stewart et al., 2010). The PTPN11 gene is also located in the Ras/MAPK pathway which is associated with the NSML phenotype and variants found in NSML patients in this gene disrupt the RAS pathway function as demonstrated by mouse and zebrafish models (Aoki et al., 2016; Marin et al., 2011; Rauen, 2013; Stewart et al., 2010). Variants observed in NSML patients are predicted to be neomorphic alleles with reduced phosphatase activity (e.g. p.Thr468Met) (Edouard et al., 2010; Hanna et al., 2006; Keilhack, David, McGregor, Cantley, & Neel, 2005; Kontaridis, Swanson, David, Barford, & Neel, 2006; Oishi et al., 2006; Oishi et al., 2009; Tartaglia et al., 2006; Yu et al., 2014)