Submissions for variant NM_001308093.3(GATA4):c.1232A>T (p.Tyr411Phe)

dbSNP: rs909187176

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001053405	SCV001217663	uncertain significance	Atrioventricular septal defect 4	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 410 of the GATA4 protein (p.Tyr410Phe). This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with GATA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 849443). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Baylor Genetics	RCV001334993	SCV001528015	uncertain significance	Testicular anomalies with or without congenital heart disease	2018-02-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001574796	SCV001801671	uncertain significance	not provided	2022-08-26	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Genetic Services Laboratory, University of Chicago	RCV001819774	SCV002068818	uncertain significance	not specified	2021-05-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GATA4 gene demonstrated a sequence change, c.1229A>T, in exon 7 that results in an amino acid change, p.Tyr410Phe. This sequence change has been described in gnomAD with a frequency of 0.064% in the East Asia sub-population (dbSNP rs909187176). The p.Tyr410Phe change affects a moderately conserved amino acid residue located in a domain of the GATA4 protein that is known to be functional. The p.Tyr410Phe substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with GATA4-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Tyr410Phe change remains unknown at this time.
Ambry Genetics	RCV003160424	SCV003855028	uncertain significance	Cardiovascular phenotype	2022-12-25	criteria provided, single submitter	clinical testing	The p.Y410F variant (also known as c.1229A>T), located in coding exon 6 of the GATA4 gene, results from an A to T substitution at nucleotide position 1229. The tyrosine at codon 410 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.