Inheritance

Autosomal dominant

Prevalence

 1:100 births (non-specific)

Source: American Heart Association About Congenital Heart Defects

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

GenCC- Orphanet Supportive (9/14/2021); BabySeq- Moderate (Familial atrial fibrillation); OMIM- Congenital heart defects, multiple types, 5

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID: 23031282 Family 1 II-1 c.394 C>G; p.R132G, Absent in gnomAD, ASD in proband and affected mother. Family 2 III-3 c.569T>C; p.V190A, Absent in gnomAD, TOF. Family members with DORC and VSD. Family 3 II-2 c.667A>C; p.A266P, Absent in gnomAD, TOF. Inherited from unaffected father. Family 4 III-1 c.821A>G; p.H274R, Absent in gnomAD, VSD. Scoring: 4x0.1=0.4 variant points

PMID: 22961344 Family 1 III-2 c.595C>G; p.L199V, Absent in gnomAD, Subarterial VSD in all affected family members. Functional data- “These results demonstrate that the p.L199V-mutant GATA5 is associated with significantly reduced activation activity compared with its wild-type counterpart” Scoring: 0.1 + 0.5 for additional functional data = 0.6 variant points

PMID: 23289003 p.R187G, Absent in gnomAD, TOF Inherited from affected family members. p.H207R, Absent in gnomAD, TOF, Inherited from affected family members. Functional data- “both GATA5 mutants are associated with significantly reduced activation activity compared with their wild-type counterpart”. Scoring 2 x 0.1, + 0.5 x 2 for additional functional data = 1.2 variant points

PMID: 27066509 Homozygous p. Tyr142His (Recurrent), Conflicting: Likely benign/VUS, Gnomad: 0.0004921, DORV, small VSD, mild PS., Inherited from unaffected parents (both parents carried the variant). p.T289A, Absent in gnomad, AV canal. p.L233P (recurrent), Likely bening, Gnomad: 0.001374, Coarctation. p.G166S (recurrent), Benign, Gnomad: 0.001118, Single ventricle, TOF, Found in 2 patients. p.T67P, Benign, Gnomad: 0.1526, AS, Coarctation, VSD< PDA, AV canal, Found in 6 patients and 4 controls. p.R61S, Absent in gnomad, VSD. p.G63A, Absent in gnomad, Pulmonary stenosis. Scoring (only using variants absent in gnomAD) 3 x 0.1 = 0.3 variant points

PMID: 24638895 Family 1 II-6 c.46T>G; p.Y16D, Absent in gnomAD, Bicuspid aortic valve (BAV); relatives with VSD, AS and Afib. Family 2 II-1, c.754A>C; p.T252P, Absent in gnomAD, BAV; father with aortic stenosis. Scoring 2 x 0.1 = 0.2 variant points

PMID: 30229885 p.Arg202Gln, VUS, Gnomad: 0.00002475, BAV, Enriched in cases versus controls. Scoring 1 x 0.1 = 0.1 variant points

Segregation Evidence:

PMID: 24638895- 3 segregations; PMID: 23031282- 4 segregations; PMID: 22961344- 3 segregations; PMID: 23289003- 3 segregations. Total = 13 total segregations , LOD score = 3.912, 2 segregation points

Case/Control Evidence:

Experimental Evidence:

http://genesdev.cshlp.org/content/13/22/2983: Zebrafish model demonstrating that GATA5 regulates expression of nkx2.5 and is important for normal cardiac development. 2 points for model
https://www.ncbi.nlm.nih.gov/pubmed/10501969: Expressed in developing heart – 0.5

PMID: 24573614- 2 somatic variants seen in cardiac tissue in pts with TOF. In HEK-293 cells, “two GATA5 mutants are associated with markedly reduced activation activity compared to their wild-type counterpart” 1 point for cell culture model

https://www.ncbi.nlm.nih.gov/pubmed/21633169: GATA5 -/- mice show multiple cardiac abnormalities- 2 points for non-human model

Source:

Clinical Validity Points Total

10.3

Source: See above

Clinical Validity Classification

MODERATE

Source: See above

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link