Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GATA3 : hypoparathyroidism-deafness-renal disease syndrome

HGNC:4172 | MONDO_0007797
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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 1
1.5
1.5
Döneray H et al. 2015 Jun (PMID:26316437);
Proband with predicted or proven null variant 1.5 0-2 10 5 7.5 7.5
Van Esch H et al. 2000 Jul 27 (PMID:10935639); Muroya K et al. 2001 Jun (PMID:11389161); Kita M et al. 2018 Nov 2. (PMID:30396722); Lin YH et al. 2015 Jan (PMID:25771973);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
2.5
2.5
Belge H et al. 2017 May 1 (PMID:27387476); Ohta M et al. 2011 Jan (PMID:21120445); Muroya K et al. 2001 Jun (PMID:11389161);
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 3.61 2
Kita M et al. 2018 Nov 2. (PMID:30396722); Lin YH et al. 2015 Jan (PMID:25771973);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.61    
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 1 0.5
Han SI et al. 2015 Aug 15 (PMID:25917456);
Expression 0.5 0 - 2 1 0.5
Luo XJ et al. 2013 Sep 15 (PMID:23666531);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Han SI et al. 2015 Aug 15 (PMID:25917456); Luo XJ et al. 2013 Sep 15 (PMID:23666531);
Models Non-human model organism 2 0 - 4 4 3 3.5 3.5
Pandolfi PP et al. 1995 Sep (PMID:7550312); Luo XJ et al. 2013 Sep 15 (PMID:23666531); Bardhan T et al. 2019 May 8. (PMID:31069810);
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) 5.5

 


 

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 5.5 17.5 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
06/19/2019
EXPERT CURATION (DATE)
Definitive
06/18/2019
EVIDENCE SUMMARY
GATA3 was reported in relation to autosomal dominant hypoparathyroidism-deafness-renal disease syndrome in 1995 (Pandolfi PMID: 7550312). At least 8 unique variant (missense, nonsense, frameshift, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, segregation and experimental data. Variants in this gene have been reported in at least 9 probands in 7 publications (PMIDs: 10935639, 11389161, 21120445, 26316437, 25771973, 27387476, 30396722). More evidence is available in the literature, but the maximum score for genetic evidence (12 pt.) has been reached. In summary, GATA3 is definitively associated with autosomal dominant hypoparathyroidism-deafness-renal disease 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 Gene Curation Expert Panel on 6/18/19.