Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ATP6V1B1 : renal tubular acidosis, distal, with progressive nerve deafness

HGNC:853 | MONDO_0009968
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 6
12
12
Karet FE et al. 1999 Jan (PMID:9916796);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Tian C et al. 2017 Oct 01 (PMID:28934385);
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
11/28/2018
EXPERT CURATION (DATE)
Definitive
12/19/2017
EVIDENCE SUMMARY
The relationship between ATP6V1B1 and autosomal recessive renal tubular acidosis with deafness was evaluated using the ClinGen Clinical Validity Framework as of 12/13/2017. Variants in ATP6V1B1 were first reported in humans with this disease as early as 1999 (Karet et al.). At least 6 variants (missense, nonsense, frameshift) have been reported in humans. Many more papers have been published since the original Kerat et al. 1999 paper with autosomal recessive renal tubular acidosis and hearing loss cases due to ATP6V1B1 variants, however the maximum score for genetic evidence has been reached. The majority of patients have LOF variants, with some missense cases. There is one mouse model with a homozygous missense ATP6V1B1 variant resulting in hearing loss, however there is a knockout model in which the mice have renal tubular acidosis and normal hearing (PMID 28934385, 12782355). Hearing loss prevalence is about 90%. In summary, ATP6V1B1 is definitively associated with autosomal recessive renal tubular acidosis with deafness. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.