Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC52A2 : brown-Vialetto-van Laere syndrome 2

HGNC:30224 | MONDO_0013867
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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 1
2
10
Foley AR et al. 2014 Jan (PMID:24253200);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 8
8
Johnson JO et al. 2012 Sep (PMID:22740598); Haack TB et al. 2012 Nov (PMID:22864630); Ciccolella M et al. 2013 Feb (PMID:23243084); Foley AR et al. 2014 Jan (PMID:24253200); Gudbjartsson DF et al. 2015 May (PMID:25807286); Manole A et al. 2017 Nov 1 (PMID:29053833);
Segregation Evidence   Summed LOD Family Count 2 2  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 4.91 1
Srour M et al. 2014 Nov (PMID:24616084);
Total Summed LOD Score 4.91    
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
Yao Y et al. 2010 Jul (PMID:20463145);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Ciccolella M et al. 2013 Feb (PMID:23243084);
Functional Alteration Patient cells 1 0 - 2 2 1
1
2
Ciccolella M et al. 2013 Feb (PMID:23243084);
Non-patient cells 0.5 0 - 1 2 1
Haack TB et al. 2012 Nov (PMID:22864630); Foley AR et al. 2014 Jan (PMID:24253200);
Models Non-human model organism 2 0 - 4 4
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) 3

 


 

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 3 15 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
10/03/2018
EXPERT CURATION (DATE)
Definitive
07/09/2018
EVIDENCE SUMMARY
The SLC52A2 gene has been associated with autosomal recessive Brown-Vialetto-van Laere syndrome using the ClinGen Clinical Validity Framework as of 9/12/2017. This association was made using case-level data only. At least 12 missense and nonsense variants have been reported in humans. SLC52A2 was first associated with this disease in humans as early as 2012 (Johnson et al.). Association is seen in at least 10 probands in 7 publications (22740598, 22864630, 23243084, 24616084, 24253200, 25807286, 29053833). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by expression studies and in vitro assays. In summary, SLC52A2 is definitively associated with autosomal recessive Brown-Vialetto-van Laere syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 7/9/2018.