ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.655G>A (p.Ala219Thr)

gnomAD frequency: 0.00001  dbSNP: rs760305842
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000644451 SCV000766147 uncertain significance Atrial septal defect 7 2023-09-10 criteria provided, single submitter clinical testing 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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 219 of the NKX2-5 protein (p.Ala219Thr). This variant is present in population databases (rs760305842, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. ClinVar contains an entry for this variant (Variation ID: 536138). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NKX2-5 protein function.
Ambry Genetics RCV002360590 SCV002665266 uncertain significance Cardiovascular phenotype 2022-03-21 criteria provided, single submitter clinical testing The p.A219T variant (also known as c.655G>A), located in coding exon 2 of the NKX2-5 gene, results from a G to A substitution at nucleotide position 655. The alanine at codon 219 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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.

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