ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.494C>T (p.Ala165Val)

gnomAD frequency: 0.00004  dbSNP: rs984722259
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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 RCV001955420 SCV002214552 uncertain significance Atrial septal defect 7 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the NKX2-5 protein (p.Ala165Val). This variant is present in population databases (no rsID available, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital heart disease (PMID: 29368431). ClinVar contains an entry for this variant (Variation ID: 1437112). 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. 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.
GeneDx RCV002275291 SCV002562606 uncertain significance not provided 2022-02-09 criteria provided, single submitter clinical testing Reported as a paternally-inherited variant in an individual with a CHD (hypoplastic left heart variant); father was unaffected by self-report (Hauser et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29368431)
Ambry Genetics RCV002334934 SCV002642590 uncertain significance Cardiovascular phenotype 2018-10-31 criteria provided, single submitter clinical testing The p.A165V variant (also known as c.494C>T), located in coding exon 2 of the NKX2-5 gene, results from a C to T substitution at nucleotide position 494. The alanine at codon 165 is replaced by valine, an amino acid with similar properties. This variant was reported in an individual with hypoplastic left heart syndrome and in his unaffected father (Hauser NS et al. Mol Genet Genomic Med, 2018 03;6:200-212). This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics RCV002484679 SCV002788016 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 2022-02-11 criteria provided, single submitter clinical testing

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