Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

COL4A5 : Alport syndrome

HGNC:2207 | MONDO_0018965
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 4 6 6
Liu JH et al. 2017 May 18 (PMID:28542346); Wang Q et al. 2013 Jan 10 (PMID:23085274); Pan X et al. 2004 May (PMID:14993485); Cruz-Robles D et al. 1999 Sep (PMID:10563487);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
6
6
Liu JH et al. 2017 May 18 (PMID:28542346); Yokota K et al. 2017 Oct (PMID:27796712); Abe Y et al. 2016 (PMID:27725546); Zholdybayeva EV et al. 2014 Dec (PMID:25572247);
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 3.91 1
Zholdybayeva EV et al. 2014 Dec (PMID:25572247);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.91    
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
1
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 1
Zehnder AF et al. 2005 Nov (PMID:16301374);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4 4
Rheault MN et al. 2004 Jun (PMID:15153557); Hashikami K et al. 2019 Mar (PMID:30582011);
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 12 5 17 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
03/19/2019
EXPERT CURATION (DATE)
Definitive
03/19/2019
EVIDENCE SUMMARY
COL4A5 was first reported in relation to X-linked Alport syndrome in 1990 (Myers et al., 2339699). Eight missense, frameshift, nonsense and splice-site variants reported in humans were included in this curation, however approximately 1000 pathogenic or likely pathogenic variants in this gene have been reported in ClinVar. 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 8 probands in 7 publications (10563487, 14993485, 23085274, 25572247, 27725546, 28542346, 27796712). Variants in this gene segregated with disease in 18 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by knock-in mouse models and expression studies in humans (15153557, 30582011, 16301374). In summary, COL4A5 is definitely associated with X-linked Alport syndrome. 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 3/19/19 (SOP Version 6).