Gene Validity Curation - ClinGen Knowledge Base

Gene/Disease Pair:	PTCHD1 : non-syndromic X-linked intellectual disability
	HGNC:26392 \| MONDO_0019181
Mode of Inheritance:	X-linked inheritance (HP:0001417)
Expert Panel:	Autism and Intellectual Disability 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	4	4	Chaudhry A et al. 2015 Sep (PMID:25131214); Farwell KD et al. 2015 Jul (PMID:25356970);
				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	3	3	Chaudhry A et al. 2015 Sep (PMID:25131214); Grozeva D et al. 2015 Dec (PMID:26350204);
			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)										7
Experimental Evidence	Evidence Category			Evidence Type			Guidelines			Points		PMIDs/Notes
							Default	Range	Max	Total	Counted
	Function			Biochemical Function			0.5	0 - 2	2	0	0.5	Noor A et al. 2010 Sep 15 (PMID:20844286);
				Protein Interaction			0.5	0 - 2
				Expression			0.5	0 - 2		0.5		Noor A et al. 2010 Sep 15 (PMID:20844286); Wells MF et al. 2016 Apr 7 (PMID:27007844);
	Functional Alteration			Patient cells			1	0 - 2	2
				Non-patient cells			0.5	0 - 1
	Models			Non-human model organism			2	0 - 4	4	2	2	Wells MF et al. 2016 Apr 7 (PMID:27007844);
				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)										2.5

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

2.5

9.5

YES

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)

Moderate

09/17/2018

MODIFY CALCULATED CLASSIFICATION

YES

MODIFIED CLASSIFICATION (DATE)

Definitive

09/17/2018

REASON(S) FOR CHANGE

PMID 25131214: Three affected patients (from families F, I, and N) described in this publication had large deletions involving only the PTCHD1 gene that could not be entered in the GCI, each contributing 1.5 points to the final genetic evidence score. PMID 28934986: One affected patient (patient 2) described in this publication had a large deletion encompassing exons 2-3 of the PTCHD1 gene that could not be entered in the GCI, contributing 1.5 points to the final genetic evidence score. PMID 20844286: Biochemical functional studies in this publication (evidence entered into GCI but not scored) awarded 0.25 points. Including the above evidence: Total genetic evidence points calculated = 12; Total experimental evidence points calculated = 2.75; Total awarded points = 14.75; Replication over time = Yes; Final classification = Definitive.

EXPERT CURATION (DATE)

Definitive

09/19/2018

EVIDENCE SUMMARY

Multiple independent reports of affected individuals with deleterious PTCHD1 variants, in addition to functional and mouse model evidence, support a compelling link between deleterious variants in PTCHD1 and X-linked intellectual disability.

Knowledge Base

Gene Validity Classification Summary

PTCHD1 : non-syndromic X-linked intellectual disability