Gene Validity Curation - ClinGen Knowledge Base

Gene Validity Classification Summary

Gene/Disease Pair:	BRAF : Costello syndrome
	HGNC:1097 \| MONDO_0009026
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	0	0	Rauen KA et al. 2006 Aug 1 (PMID:16804887);
			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

07/24/2018

MODIFY CALCULATED CLASSIFICATION

YES

MODIFIED CLASSIFICATION (DATE)

Disputed

07/24/2018

REASON(S) FOR CHANGE

No score-able cases have been described but there have been assertions made.

EXPERT CURATION (DATE)

Disputed

07/24/2018

EVIDENCE SUMMARY

Only one study to date has identified variants in BRAF in patients diagnosed with suspected Costello syndrome. However, due to lack of further evidence of impact of these variants as well as variable expressivity, age of ascertainment and outdated clinical assessments of affected individuals, these cases were not scored and, therefore, the evidence for this association is Disputed. Furthermore, the HRAS gene is believed to be the only gene definitively associated with Costello syndrome (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007).

Knowledge Base

Gene Validity Classification Summary

BRAF : Costello syndrome