Gene Validity Classification Summary

Gene/Disease Pair:

LOXHD1 : nonsyndromic genetic deafness

HGNC:26521 | MONDO_0019497
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 9
Edvardson S et al. 2011 May (PMID:21465660); Grillet N et al. 2009 Sep (PMID:19732867); Sloan-Heggen CM et al. 2016 Apr (PMID:26969326);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Sloan-Heggen CM et al. 2016 Apr (PMID:26969326);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.93 2
Edvardson S et al. 2011 May (PMID:21465660); Grillet N et al. 2009 Sep (PMID:19732867);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.93    
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 1 0.5
Grillet N et al. 2009 Sep (PMID:19732867);
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
Grillet N et al. 2009 Sep (PMID:19732867);
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) 2.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 2.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between LOXHD1 and autosomal recessive nonsyndromic genetic deafness was evaluated using the ClinGen Clinical Validity Framework as of 11/15/2017. Variants in LOXHD1 were first reported in humans with this disease as early as 2009 (Grillet et al., PMID 19732867). At least 16 unique variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 11 probands in 6 publications (PMIDs 26969326, 21465660, 19732867). Variants in this gene segregated with disease in 13 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is thought to be that loss of function of the LOXHD1 protein is deleterious to hair cell function (PMID: 19732867). This gene-disease association is supported by animal an animal model that also demonstrated expression of LOXHD1 in the ear (PMID: 19732867). Studies have also identified this gene to be related to dominant late-onset Fuchs corneal dystrophy (PMID: 27121161, 22341973, 23585771). In summary, LOXHD1 is definitively associated with ARNSHL. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 5/8/2018​.