Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

LHFPL5 : nonsyndromic genetic deafness

HGNC:21253 | 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 5
6
8
Shabbir MI et al. 2006 Aug (PMID:16459341); Kalay E et al. 2006 Jul (PMID:16752389); Bensaïd M et al. 2011 Nov-Dec (PMID:21816241); Shahin H et al. 2010 Apr (PMID:19888295);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
2
Shabbir MI et al. 2006 Aug (PMID:16459341); Kalay E et al. 2006 Jul (PMID:16752389); Komara M et al. 2016 Feb (PMID:26437881); Ammar-Khodja F et al. 2015 May (PMID:26029705);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 8.21 2
Shabbir MI et al. 2006 Aug (PMID:16459341); Kalay E et al. 2006 Jul (PMID:16752389);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 8.21    
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) 9.5
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
Protein Interaction 0.5 0 - 2 1 0.5
Zhao B et al. 2014 Dec 03 (PMID:25467981);
Expression 0.5 0 - 2 1 0.5
Shabbir MI et al. 2006 Aug (PMID:16459341);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 5 4
Longo-Guess CM et al. 2005 May 31 (PMID:15905332); Cosetti M et al. 2008 Nov (PMID:19102128); Beurg M et al. 2015 Feb 03 (PMID:25550511);
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 9.5 5 14.5 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
11/26/2018
EXPERT CURATION (DATE)
Definitive
04/24/2018
EVIDENCE SUMMARY
The LHFPL5 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/27/2017. This association was made using case-level data only. At least 8 missense, nonsense, and frameshift variants have been reported in humans. LHFPL5 was first associated with this disease in humans as early as 2006 (Shabbir et al.). Association is seen in at least 9 probands in 6 publications (16459341, 16752389, 21816241, 19888295, 26437881, 26029705). Variants in this gene segregated with disease in 24 additional family members. This gene-disease association is supported by 2 mouse models, a fly model, expression studies and protein interaction studies. In summary, LHFPL5 is definitively associated with autosomal recessive nonsyndromic hearing loss.