Gene Validity Curation - ClinGen Knowledge Base

Gene Validity Classification Summary

Gene/Disease Pair:	RRAS : Noonan syndrome-like disorder with loose anagen hair
	HGNC:10447 \| MONDO_0011899
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
				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

06/06/2018

MODIFY CALCULATED CLASSIFICATION

YES

MODIFIED CLASSIFICATION (DATE)

No Reported Evidence

06/06/2018

REASON(S) FOR CHANGE

EXPERT CURATION (DATE)

No Reported Evidence

06/06/2018

EVIDENCE SUMMARY

No published evidence to date has implicated an association between RRAS variants and NS/LAH.

Knowledge Base

Gene Validity Classification Summary

RRAS : Noonan syndrome-like disorder with loose anagen hair