Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ADGRV1 : nonsyndromic genetic deafness

HGNC:17416 | MONDO_0019497
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 10
0
0
Shearer AE et al. 2013 Sep (PMID:23804846); Gu X et al. 2015 Jun (PMID:24853665); Bademci G et al. 2016 Apr (PMID:26226137); Sloan-Heggen CM et al. 2015 Dec (PMID:26445815); Yang T et al. 2013 Jun 14 (PMID:23767834); Sommen M et al. 2016 Aug (PMID:27068579); Bousfiha A et al. 2017 Oct (PMID:28951997);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 7
0
Neveling K et al. 2013 Dec (PMID:24123792); Haraksingh RR et al. 2014 Dec 20 (PMID:25528277); Kim NK et al. 2015 Nov (PMID:25719458); Gu X et al. 2015 Jun (PMID:24853665); Almontashiri NAM et al. 2018 Apr (PMID:29048421); Yang T et al. 2013 Jun 14 (PMID:23767834); Sommen M et al. 2016 Aug (PMID:27068579);
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) 0
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
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) 0

 


 

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 0 0 0 NO
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)
No Classification
03/19/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
03/19/2019
REASON(S) FOR CHANGE
Evidence disputing this gene-disease relationship includes lack of age information, lack of clinical examination history, and high allele frequency of variants in population databases. Of note, this gene has also been implicated in Usher syndrome Type 2. This has been assessed separately as Definitive. The mechanism of disease of ADGRV1-Usher syndrome Type 2 is homozygous loss of function, which is consistent with the variants reported in ADGRV1-nonsyndomic hearing loss patients.
EXPERT CURATION (DATE)
Disputed
03/19/2019
EVIDENCE SUMMARY
ADGRV1, previously known as GPR98, was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2013 (Yang et al., 23767834). At least 27 unique variants (missense, nonsense, frameshift, splice-site) have been reported in humans. Variants in this gene have been reported in at least 17 probands in 11 publications (23804846, 24123792, 23767834, 25528277, 25719458, 24853665, 29048421, 26226137, 26445815, 27068579, 28951997). Evidence disputing this gene-disease relationship includes lack of age information, lack of clinical examination history, and high allele frequency of variants in population databases. Of note, this gene has also been implicated in Usher syndrome Type 2. This has been assessed separately as Definitive. The mechanism of disease of ADGRV1-Usher syndrome Type 2 is homozygous loss of function, which is consistent with the variants reported in ADGRV1-nonsyndomic hearing loss patients. In summary, there is convincing evidence disputing the relationship between ADGRV1 and autosomal recessive nonsyndromic hearing loss. More evidence is needed to either support or refute the role ADGRV1 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 3/19/19 (SOP Version 6).