Submissions for variant NM_001308093.3(GATA4):c.487C>T (p.Pro163Ser)

gnomAD frequency: 0.00004  dbSNP: rs387906769

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000023004	SCV000746750	pathogenic	Tetralogy of Fallot	2017-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV000023002	SCV000825496	uncertain significance	Atrioventricular septal defect 4	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the GATA4 protein (p.Pro163Ser). This variant is present in population databases (rs387906769, gnomAD 0.05%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 17643447, 18672102, 20874241, 23626780, 27139165, 28161810, 31513339). ClinVar contains an entry for this variant (Variation ID: 30099). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATA4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001753426	SCV001985407	uncertain significance	not provided	2019-09-11	criteria provided, single submitter	clinical testing	Reported in association with congenital heart defects (Rajagopal et al., 2007; Zhang et al., 2008; Peng et al., 2010; Wang et al., 2013; Wang et al., 2016; Liu et al., 2017); Did not segregate with disease in one family in which all affected family members harbored a variant in the ACTC1 gene (Wang et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21110066, 23626780, 17643447, 18672102, 27139165, 28161810, 31513339)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470717	SCV002768601	uncertain significance	Testicular anomalies with or without congenital heart disease	2020-10-15	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS- 3B Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. For 46,XY disorders of sex development, incomplete penetrance was suggested in PMID:29670578. For cardiac conditions, a large 3 generation family showed high but incomplete penetrance and variable expressivity (PMID:20347099). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (gnomAD (v2.1.1): 0.00006185 (7 Het, 0 Hom). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(Pro163Arg): 0.00000883 (1 Het, 0 Hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the GATA-N domain (GATA-type transcription activator, N-terminal) (DECIPHER, NCBI Conserved domains, RCSB-PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity: p.(Pro163Arg): 1 submission in ClinVar as VUS (Atrioventricular septal defect). (N) 0808 - Previous reports of pathogenicity are conflicting. All publications for this variant relate to cardiac conditions. ClinVar: Conflicting interpretations of pathogenicity: 5 submissions: 4x Pathogenic + 1x VUS, the most recent being VUS. LOVD3: VUS and Likely benign. PMID: 28471988: Meta-studies indicate that this variant is not associated with disease (congenital heart disease). PMID: 23626780: this variant appeared in many controls (cardiac study). (N) 0905 - No segregation evidence has been identified for this variant, in association with a disorder of sex development (DSD). (N) 1002 - Moderate functional evidence supporting abnormal protein function. This variant was shown to have impaired binding with ZFMP2 (PMID: 31513339). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Laan Lab, Human Genetics Research Group, University of Tartu	RCV003991569	SCV004239148	likely pathogenic	Male infertility with azoospermia or oligozoospermia due to single gene mutation	2023-09-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001753426	SCV004701681	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GATA4: PP2, PP3, PS3:Supporting, BS2
OMIM	RCV000023002	SCV000044293	pathogenic	Atrioventricular septal defect 4	2010-12-01	no assertion criteria provided	literature only
OMIM	RCV000023003	SCV000044294	pathogenic	Ventricular septal defect 1	2010-12-01	no assertion criteria provided	literature only
OMIM	RCV000023004	SCV000044295	pathogenic	Tetralogy of Fallot	2010-12-01	no assertion criteria provided	literature only