ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.842C>A (p.Ala281Glu)

gnomAD frequency: 0.00001  dbSNP: rs1206339157
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001038821 SCV001202319 uncertain significance Atrial septal defect 7 2023-01-17 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 281 of the NKX2-5 protein (p.Ala281Glu). 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. 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. ClinVar contains an entry for this variant (Variation ID: 837477). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%).
Ambry Genetics RCV002409381 SCV002675834 uncertain significance Cardiovascular phenotype 2023-01-21 criteria provided, single submitter clinical testing The p.A281E variant (also known as c.842C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 842. The alanine at codon 281 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002489557 SCV002794427 uncertain significance Atrial septal defect 7; Conotruncal heart malformations; Hypothyroidism, congenital, nongoitrous, 5; Tetralogy of Fallot; Ventricular septal defect 3; Hypoplastic left heart syndrome 2 2021-09-18 criteria provided, single submitter clinical testing

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