Gene Validity Curation - ClinGen Knowledge Base

Gene Validity Classification Summary

Gene/Disease Pair:	RAF1 : Noonan syndrome with multiple lentigines
	HGNC:9829 \| 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	2	2	Pandit B et al. 2007 Aug (PMID:17603483);
				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	2	2	Pandit B et al. 2007 Aug (PMID:17603483); Carcavilla A et al. 2013 May (PMID:24775816); Kuburović V et al. 2011 Nov-Dec (PMID:22389993);
			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)										4
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		Pandit B et al. 2007 Aug (PMID:17603483); Kobayashi T et al. 2010 Mar (PMID:20052757);
	Models			Non-human model organism			2	0 - 4	4		0
				Cell culture model			1	0 - 2		0		Dhandapany PS et al. 2011 Jul (PMID:21440552);
	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

0.5

4.5

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)

Limited

07/25/2018

EXPERT CURATION (DATE)

Limited

07/25/2018

EVIDENCE SUMMARY

There was only sufficient evidence in the literature for the RAF1:NSML association to be classified as Limited. Only two variants with supporting evidence for pathogenicity (one de novo) in the gene have been found in individuals with NSML (Carcavilla et al., 2013; Kuburovic, Vukomanovic, Carcavilla, Ezquieta-Zubicaray, & Kuburovic, 2011; Pandit et al., 2007). The RAF1 gene is also located in the Ras/MAPK pathway which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013).

Knowledge Base

Gene Validity Classification Summary

RAF1 : Noonan syndrome with multiple lentigines