Gene Validity Classification Summary

Gene/Disease Pair:

SLC52A3 : Brown-Vialetto-van Laere syndrome

HGNC:16187 | MONDO_0000406
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss 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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 6
10.5
12
Green P et al. 2010 Mar 12 (PMID:20206331); Bosch AM et al. 2011 Feb (PMID:21110228); Cosgrove J et al. 2015 Jan (PMID:25462087); Manole A et al. 2017 Nov 1 (PMID:29053833);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 15
1.9
Green P et al. 2010 Mar 12 (PMID:20206331); Bosch AM et al. 2011 Feb (PMID:21110228); Ciccolella M et al. 2012 Dec (PMID:22824638); Manole A et al. 2017 Nov 1 (PMID:29053833);
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
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 Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
1.5
Subramanian VS et al. 2017 Aug 1 (PMID:28637675);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1
Intoh A et al. 2016 May 1 (PMID:26976849);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Subramanian VS et al. 2017 Aug 1 (PMID:28637675);
Models Non-human model organism 2 0 - 4 4 3 4 4
Manole A et al. 2017 Nov 1 (PMID:29053833); Yoshimatsu H et al. 2016 Jun 8 (PMID:27272163); Intoh A et al. 2016 May 1 (PMID:26976849);
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) 6

 


 

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 6 18 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
12/06/2018
EXPERT CURATION (DATE)
Definitive
09/18/2018
EVIDENCE SUMMARY
The relationship between SLC52A3 and autosomal recessive Brown-Vialetto-van Laere syndrome (BVVL) was evaluated using the ClinGen Clinical Validity Framework as of 9/12/2018. Variants in SLC52A3 were first reported in humans with this disease as early as 2010 (Green et al., PMID 20206331). At least 25 variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, case-control data, segregation data, and mouse models, a drosophila model, biochemical function studies implicating the gene's role in riboflavin uptake, and functional alteration studies showing that alteration to the gene impairs riboflavin uptake which appears to be the mechanism for disease. Variants in this gene have been reported in at least 22 probands in 5 publications (PMIDs: 29053833, 25462087, 21110228, 20206331, 22824638). Variants in this gene segregated with disease in 2 additional family members. In summary, SLC52A3 is definitively associated with autosomal recessive Brown-Vialetto-van Laere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 9/18/2018.