Gene Validity Classification Summary

Gene/Disease Pair:

BCS1L : Bjornstad syndrome

HGNC:1020 | MONDO_0009872
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 4
8
12
Hinson JT et al. 2007 Feb 22 (PMID:17314340); Zhang J et al. 2015 Jul 15 (PMID:25895478); Shigematsu Y et al. 2017 Jun (PMID:28105683);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
5
Hinson JT et al. 2007 Feb 22 (PMID:17314340); Siddiqi S et al. 2013 Dec (PMID:24172246); Falco M et al. 2017 May (PMID:28322498);
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 4.59 1
Hinson JT et al. 2007 Feb 22 (PMID:17314340);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.59    
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
Hinson JT et al. 2007 Feb 22 (PMID:17314340);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Hinson JT et al. 2007 Feb 22 (PMID:17314340);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Hinson JT et al. 2007 Feb 22 (PMID:17314340);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Hinson JT et al. 2007 Feb 22 (PMID:17314340);
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
10/02/2018
EXPERT CURATION (DATE)
Definitive
07/09/2018
EVIDENCE SUMMARY
The BCS1L gene has been associated with autosomal recessive Bjornstad syndrome using the ClinGen Clinical Validity Framework as of 12/13/16. This association was made using case-level data only. At least 12 missense, splice site, and frameshift variants have been reported in humans. BCS1L was first associated with this disease in humans as early as 2007 (Hinson et al.). Association is seen in at least 9 probands in 5 publications (17314340, 24172246, 25895478, 28322498, 28105683). Variants in this gene segregated with disease in 13 additional family members. This gene-disease association is supported by experimental evidence performed by Hinston et al. 2007. In summary, BCS1L is definitively associated with autosomal recessive Bjornstad syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 7/9/18.