Gene Validity Curation

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: Intellectual Disability and Autism
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
Kim SJ et al. 2002 (PMID:11920155);
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
Veenstra-Vanderweele J et al. 2009 Jun (PMID:19960097);
Non-patient cells 0.5 0 - 1 0.5
Prasad HC et al. 2009 Jan 27 (PMID:18957375);
Models Non-human model organism 2 0 - 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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 1.5 1.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
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. The gene impact for each of these three variants has yet to be specified by a ClinGen ID/Autism expert and therefore cannot yet be scored to support this gene-disease association. If included in scoring the total genetic evidence with a conservative 0.5 points awarded to each of these variants would result in a score of 1.5 for a "proband with other variant type with some evidence of gene impact". However this would still result in a final score of 3 - Limited classification.