Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BSND : Bartter disease type 4a

HGNC:16512 | MONDO_0011242
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hearing Loss
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
10
12
Birkenhäger R et al. 2001 Nov (PMID:11687798); de Pablos AL et al. 2014 May (PMID:23110775); Zaffanello M et al. 2006 Jun (PMID:16583241);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
2
Birkenhäger R et al. 2001 Nov (PMID:11687798); Miyamura N et al. 2003 Feb (PMID:12574213);
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
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
0.5
2
Waldegger S et al. 2002 Jun (PMID:12111250);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1.5
Birkenhäger R et al. 2001 Nov (PMID:11687798); Waldegger S et al. 2002 Jun (PMID:12111250);
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 2
Waldegger S et al. 2002 Jun (PMID:12111250); Estévez R et al. 2001 Nov 29 (PMID:11734858); Janssen AG et al. 2009 Jan (PMID:18776122);
Models Non-human model organism 2 0 - 4 4 1 1
Rickheit G et al. 2008 Nov 5 (PMID:18833191);
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) 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 12 5 17 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
07/12/2018
EXPERT CURATION (DATE)
Definitive
07/12/2018
EVIDENCE SUMMARY
The BSND gene has been associated with autosomal recessive Bartter syndrome using the ClinGen Clinical Validity Framework as of 12/20/2016​. This association was made using case-level data only). At least ​8 missense, start loss, deletion, and frameshift variants have been reported in humans. BSND​ was first associated with this disease in humans as early as 2001​ (Birkenhager et al.​). Association is seen in at least 10 probands in 4 publications (11687798, ​12574213, 23110775, 16583241). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. Of note, this gene has also been implicated in nonsyndromic hearing loss. Expert review determined there was not enough convincing evidence to split out this disease. This gene-disease association is supported by functional studies that exhibit the molecular basis for disease of these variants (Birkenhager et al. 2001, Waldegger et al. 2002, Janssen et al. 2009) . A BSND mouse models have also been created that exhibit the hearing loss phenotypes seen in Bartter syndrome (Rickheit et al. 2008). In summary, BSND is definitively associated with autosomal recessive Bartter syndrome. This classification was approved by the ClinGen Hearing Loss​ Working Group on 7/10/2018.