ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.448G>A (p.Val150Ile)

gnomAD frequency: 0.00001  dbSNP: rs201582515
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622055 SCV000735242 uncertain significance Cardiovascular phenotype 2015-11-25 criteria provided, single submitter clinical testing The p.V150I variant (also known as c.448G>A), located in coding exon 2 of the NKX2-5 gene, results from a G to A substitution at nucleotide position 448. The valine at codon 150 is replaced by isoleucine, an amino acid with highly similar properties. This variant was described in an individual with multiple ventricular septal defects, who also harbored another genetic alteration in ZIC3 (De Luca A et al. Heart. 2010;96(9):673-7). This variant was previously reported in the SNPDatabase as rs201582515. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.51% (1/196) Tuscan alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001227312 SCV001399665 uncertain significance Atrial septal defect 7 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 150 of the NKX2-5 protein (p.Val150Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with transposition of the great arteries (PMID: 19933292). ClinVar contains an entry for this variant (Variation ID: 518495). 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 NKX2-5 protein function with a negative 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.
AiLife Diagnostics, AiLife Diagnostics RCV002223229 SCV002501120 uncertain significance not provided 2022-01-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002491307 SCV002793735 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 2021-07-20 criteria provided, single submitter clinical testing

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