Gene Validity Classification Summary

Gene/Disease Pair:

SLC6A4 : complex neurodevelopmental disorder

HGNC:11050 | MONDO_0100038
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Autism and Intellectual Disability EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count 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 3
1.5
1.5
Sutcliffe JS et al. 2005 Aug (PMID:15995945);
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   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
0
Aggregate Variant Analysis 0-6 2
0
Kim SJ et al. 2002 (PMID:11920155);
Total Genetic Evidence Points (Maximum 12) 1.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count 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 1
0.5
1
Veenstra-Vanderweele J et al. 2009 Jun (PMID:19960097);
Non-patient cells 0.5 0 - 1 1 0.5
Prasad HC et al. 2009 Jan 27 (PMID:18957375);
Models Non-human model organism 2 0 - 4 4 4 0.5 0.5
Jennings KA et al. 2006 Aug 30 (PMID:16943551); Veenstra-VanderWeele J et al. 2012 Apr 3 (PMID:22431635); Bengel D et al. 1998 Apr (PMID:9547354); Thakker DR et al. 2005 Aug (PMID:15940298);
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) 1.5

 


 

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 1.5 1.5 3 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Limited
10/09/2018
EXPERT CURATION (DATE)
Limited
05/02/2018
EVIDENCE SUMMARY
Approved by the ClinGen ID/Autism Expert Panel 5/2/18. Additional mice models are available as supplemental evidence but were not utilized in the scoring. NOTE: Three variants (Ile425Leu; Phe465Leu; and Leu550Val) listed in PMID:15995945, were noted in three unrelated families and identified as 3 different rare SLC6A4 variants that segregated with the disorder, suggesting that SLC6A4 represents a susceptibility locus for autism spectrum disorders. These variants in aggregate appeared to be associated with increased rigid-compulsive behaviors when viewed as a subphenotype of autism. Variant confirmation and segregation of the rare variants were determined by sequencing available family members and the original proband.