Gene Validity Curation - ClinGen Knowledge Base

Gene/Disease Pair:	RASA1 : Noonan syndrome
	HGNC:9871 \| 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
				Proband with predicted or proven null variant			1.5	0-2	10	0	0	Macmurdo CF et al. 2016 Jun (PMID:26969842);
				Proband with other variant type with some evidence of gene impact			0.5	0-1.5	7
			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

CALCULATED CLASSIFICATION

LIMITED

1-6

MODERATE

7-11

STRONG

12-18

DEFINITIVE

12-18 AND replication over time

Valid contradictory evidence (Y/N)*

CALCULATED CLASSIFICATION (DATE)

No Classification

06/07/2018

MODIFY CALCULATED CLASSIFICATION

YES

MODIFIED CLASSIFICATION (DATE)

Disputed

06/07/2018

REASON(S) FOR CHANGE

All patients reported to date have capillary malformations without additional features of a RASopathy that couldn't be explained by an alternate cause.

EXPERT CURATION (DATE)

Disputed

06/07/2018

EVIDENCE SUMMARY

There have been multiple reported cases both in the literature showing that RASA1 variants can cause cardiovascular anomalies such as capillary malformation-arteriovenous malformation syndrome (CM-AVM);(Ilari, Agosta, & Bacino, 2016; Macmurdo et al., 2016). These studies suggest that these patients may possess clinical features of NS. However, patients with additional phenotypes such as hypotonia and severe ID all possess secondary causes of disease apart from RASA1 variation. Therefore, there is no convincing genetic evidence that supports the association of RASA1 and NS. In fact, RASA1 should most likely only be associated with cardiovascular anomalies. RASA1’s association with NS is Disputed.

Knowledge Base

Gene Validity Classification Summary

RASA1 : Noonan syndrome