Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC16A2 : Allan-Herndon-Dudley syndrome

HGNC:10923 | MONDO_0010354
Mode of Inheritance: X-linked inheritance (HP:0001417)
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
4
4
Boccone L et al. 2010 Nov-Dec (PMID:20713192); Vaurs-Barrière C et al. 2009 Jan (PMID:19194886);
Proband with predicted or proven null variant 1.5 0-2 10 6.5 6.5
Dumitrescu AM et al. 2004 Jan (PMID:14661163); Schwartz CE et al. 2005 Jul (PMID:15889350); Friesema EC et al. 2004 Oct 16-22 (PMID:15488219); Namba N et al. 2008 Jul (PMID:17899191); Vaurs-Barrière C et al. 2009 Jan (PMID:19194886);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
1.6
1.6
Dumitrescu AM et al. 2004 Jan (PMID:14661163); Schwartz CE et al. 2005 Jul (PMID:15889350);
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
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) 12
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
1
1
Vatine GD et al. 2017 Jun 1 (PMID:28526555);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1
Vancamp P et al. 2017 Nov 29 (PMID:29109240);
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

 


 

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 12 2 14 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)
Definitive
08/08/2018
EXPERT CURATION (DATE)
Definitive
08/09/2018
EVIDENCE SUMMARY
The SLC16A2 gene has been associated with X-linked Allan-Herndon-Dudley syndrome using the ClinGen Clinical Validity Framework as of 8/8/2018. The affected males show high serum 3,3',5-triiodothyronine (T3 ) concentration and low serum 3,3',5'-triiodothyronine (reverse T3 or rT3) concentration, along with other phenotypes: severe cognitive deficiency, infantile hypotonia, progressive spastic quadriplegia, and joint contractures. While heterozygous female carriers do not manifest psychomotor abnormalities, they have intermediate thyroid test abnormalities between affected and normal individuals. This disease association was made using case-level data and experimental data. At least 11 variants (missense, nonsense, frameshift), either familial or de novo, were curated from six publications (PMID: 20713192, 14661163, 15488219, 17899191, 15889350, and 19194886). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The disease association was first reported in human as early as 2004 (Dumitrescu et al., 2004 PMID: 14661163). To date, 33 unique variants within SLC16A2 have been classified as Pathogenic in ClinVar. This gene-disease association is supported by animal model (chicken) and patient-derived neural cells, although mouse models do not show apparent neurological phenotype (not curated here). In summary, SLC16A2 is definitively associated with X-linked Allan-Herndon-Dudley syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. According to the curation SOP, the segregation score should downgrade from 3.0 to 1.5, because all of the LOD scores calculated in this curation are based on candidate gene sequencing instead of exome/genome or all genes sequenced in the linkage regions. SLC16A2 encodes for two potential proteins, 613 and 539 amino acids, due to two alternative start sites on exon 1, although NCBI Gene only lists the one with 539 amino acids (NM_006517.4). All of the variants described in this curation is based on NM_006517.4, therefore some of the variants may seem different from the original study.