Submissions for variant NM_001308093.3(GATA4):c.1223C>A (p.Pro408Gln)

gnomAD frequency: 0.00010  dbSNP: rs115099192

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490358	SCV000267333	uncertain significance	Atrial septal defect 2; Ventricular septal defect 1; Atrioventricular septal defect 4	2016-03-18	criteria provided, single submitter	reference population
Invitae	RCV000526826	SCV000651999	benign	Atrioventricular septal defect 4	2024-01-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195378	SCV001365727	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 TOF patient (sporadic) (Zhang 2008), in 3 individuals (het) with disorders of sexual develpment (Eggers 2016). Liu 2017 further reported this variant in 4/600 patients with conotruncal heart defects and 1/300 controls. Qian 2017 reported the variant in 2 individuals with TOF and POF (also carried V380M, previously associated with VSD))). Identified in 0.3% of East Asian chromosomes in gnomAD. Present in ClinVar (ID 30103) with conflicting interpretations (B, Uncertain significance).
GeneDx	RCV001555802	SCV001777271	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Identified in several individuals with congenital heart defects (Zhang et al., 2008; Hamanoue et al., 2009; Peng et al., 2010; Wang et al., 2010; Dinesh et al., 2011; Yoshida et al., 2016; Liu et al., 2017; Qian et al., 2017; Dixit et al., 2018; Kalayinia et al., 2019) and in healthy control individuals in published literature (Hamanoue et al., 2009; Yoshida et al., 2016; Liu et al., 2017; Qian et al., 2017); Also identified in association with early onset diabetes (Kwak et al., 2016) and disorders of sexual development, including individuals without heart anomalies (Eggers et al 2016; Igarashi et al., 2018); Functional studies show inconsistent data, including one study that found p.(P407Q) results in ~50% reduction in transactivation compared to wild type protein (Igarashi et al., 2018), whereas another study showed protein behavior similar to wild type (van den Bergen et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19678963, 26490186, 24583203, 18672102, 21110066, 20654103, 20592452, 22648249, 22959235, 26997702, 27810688, 27899157, 28161810, 28372585, 29735817, 30152191, 31115957, 21631294, 31513339, 31962012, 34426522, 32508047)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272027	SCV002557871	likely benign	Testicular anomalies with or without congenital heart disease	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA4-related cardiac disease. (I) 0107 - This gene is associated with autosomal dominant disease. A number a different cardiac conditions are caused by variants in GATA4 , however association with differences of sex development (DSD) is not well-established (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of GATA4-related cardiac disease (gnomAD (v2) 132 heterozygotes, 0 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (17 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated zinc finger DNA binding domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes at the same residue, to alanine and arginine, have previously been classified as VUS in relation to atrioventricular septal defect (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting for both cardiac and DSD conditions, however more recent reports consistently report the variant as benign in relation to DSD (ClinVar, LOVD, HGMD, OMIM, PMID: 32992319). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000023008	SCV000044299	pathogenic	Tetralogy of Fallot	2008-11-01	no assertion criteria provided	literature only
OMIM	RCV000030949	SCV000044301	pathogenic	Ventricular septal defect 1	2010-12-01	no assertion criteria provided	literature only
Reproductive Development, Murdoch Childrens Research Institute	RCV001007695	SCV001146892	benign	46,XY sex reversal 3	2019-08-26	no assertion criteria provided	research
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252768	SCV001163911	uncertain significance	Microcephaly		no assertion criteria provided	research