Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL4A6 : deafness, X-linked 6

HGNC:2208 | MONDO_0010484
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 1
Rost S et al. 2014 Feb (PMID:23714752);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 2.36 1
Rost S et al. 2014 Feb (PMID:23714752);
Total Summed LOD Score 2.36    
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) 1.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Rost S et al. 2014 Feb (PMID:23714752);
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) 0.5



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 1.5 0.5 2 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The COL4A6 gene has been associated with X-linked deafness using the ClinGen Clinical Validity Framework as of 3/6/2017. This association was made using case-level data and expression data. At least 1 unique variant (missense) have been reported in humans. COL4A6 was first associated with this disease in humans as early as 2014 (Rost et al.). Association is seen in at least 1 proband in 1 publications (23714752). Variants in this gene segregated with disease in 3 additional family members. The mechanism for disease is (unknown). Of note, this gene has also been implicated in chronic kidney disease and premature ovarian failure and diffuse leiomyomatosis in Alport syndrome, but these will be assessed separately. This gene-disease association is supported by expression studies indicating that the gene is expressed in mice and zebrafish in tissues relevant to hearing (Rost 2014). In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. In the only family described to date, males were affected by severe, congenital hearing loss and displayed malformations of the cochlea. Females carrying one copy of the variant developed mild-moderate HL during the 3rd and 4th decade of life though one female carrier was unafffected. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.