ClinVar Miner

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

gnomAD frequency: 0.00010  dbSNP: rs115099192
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Total submissions: 9
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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

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