Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SHOC2 : Noonan syndrome

HGNC:15454 | MONDO_0018997
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
0
0
Hoban R et al. 2012 Jun (PMID:22528146); Komatsuzaki S et al. 2010 Dec (PMID:20882035);
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
0
Justino A et al. 2015 Mar (PMID:24896146); Komatsuzaki S et al. 2010 Dec (PMID:20882035);
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) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
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

 


 

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 0 0 0 NO
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)
No Classification
05/31/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
05/31/2018
REASON(S) FOR CHANGE
All the cases described as NS so far, have the p.S2G variant and LAH or have not had LAH ruled out, therefore it is not convincing that these cases are different from others.
EXPERT CURATION (DATE)
Disputed
05/31/2018
EVIDENCE SUMMARY
There have been cases described in the literature with the p.Ser2Gly variant in SHOC2 who were diagnosed with NS but were not phenotyped for loose anagen hair (LAH) (Hoban, Roberts, Demmer, Jethva, & Shephard, 2012; Justino et al., 2015; Komatsuzaki et al., 2010). There has only been one NS case where LAH was assessed but not noted and this individual had sparse and curly hair. Therefore, the NS/LAH phenotype cannot be ruled out for any of these patients. The p.Ser2Gly variant has been a recurrently identified variant in cases with NS/LAH, and no other variants have been identified in these patients (Cordeddu et al., 2009; Ekvall et al., 2011; Komatsuzaki et al., 2010). In summary, this association is Disputed.