ClinVar Miner

Submissions for variant NM_005257.6(GATA6):c.706G>T (p.Gly236Cys)

dbSNP: rs904551659
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001062710 SCV001227526 uncertain significance Atrioventricular septal defect 5 2024-11-16 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 236 of the GATA6 protein (p.Gly236Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital heart defects (PMID: 34493817, 36525927). ClinVar contains an entry for this variant (Variation ID: 857098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GATA6 protein function with a positive predictive value of 80%. 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001293862 SCV001482527 uncertain significance Atrial septal defect 9 2020-12-21 criteria provided, single submitter research ACMG codes:PP3
New York Genome Center RCV001420557 SCV001622863 uncertain significance Tetralogy of Fallot 2020-05-12 criteria provided, single submitter clinical testing The c.706G>T (p.Gly236Cys) variant identified in the GATA6 gene substitutes a moderately conserved Glycine for Cystine at amino acid 236/596 (coding exon 2/7). This variant is found with low frequency in gnomAD(v3.0) (5 heterozygotes, 0 homozygotes; allele frequency: 3.56e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Neutral (Provean; score: -1.51) and Damaging (SIFT; score: 0.003) to the function of the canonical transcript. It is reported as a Variant of Uncertain Significance in ClinVar (AccessionID: RCV001062710.1), and to our current knowledge has not been reported in the literature in affected individuals. The p.Gly236 residue is within a GATA-type transcriptional activation region of the protein (residues 147-378, Pfam: Q92908), and missense variants within this region have been identified in individuals with Tetralogyof Fallot [PMID:20581743; PMID:24841381; PMID:31301121]. Given the lack of compelling evidence for its pathogenicity, the c.706G>T (p.Gly236Cys) variant identified in the GATA6 gene is reported here as a Variant of Uncertain Significance.
GeneDx RCV004726853 SCV005331605 uncertain significance not provided 2023-06-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with bicuspid aortic valve in published literature; however, additional clinical information was not provided (Williams et al., 2022); This variant is associated with the following publications: (PMID: 36525927, 34493817)

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