ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.656C>T (p.Ala219Val)

gnomAD frequency: 0.00001  dbSNP: rs104893902
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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 RCV000525369 SCV000644779 uncertain significance Atrial septal defect 7 2021-09-21 criteria provided, single submitter clinical testing Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NKX2-5 function (PMID: 15917268). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 9011). This missense change has been observed to co-occur in individuals with a different variant in NKX2-5 that has been determined to be pathogenic (PMID: 15161646), but the significance of this finding is unclear. This missense change has been observed in individuals with Tetralogy of Fallot and ventricular septal defects (PMID: 11714651, 15161646). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 219 of the NKX2-5 protein (p.Ala219Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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.
Ambry Genetics RCV002362574 SCV002664807 uncertain significance Cardiovascular phenotype 2019-02-21 criteria provided, single submitter clinical testing The p.A219V variant (also known as c.656C>T), located in coding exon 2 of the NKX2-5 gene, results from a C to T substitution at nucleotide position 656. The alanine at codon 219 is replaced by valine, an amino acid with similar properties. This variant has been detected in a proband with tetralogy of Fallot and an in an unaffected parent (Goldmuntz E et al. Circulation, 2001 Nov;104:2565-8). This variant has also been detected in probands with ventricular septal defect; however, some cases also had an additional NKX2-5 variant (Reamon-Buettner SM et al. Am. J. Pathol., 2004 Jun;164:2117-25). A yeast assay reported this variant may have mild impact on function (Inga A et al. Hum. Mol. Genet., 2005 Jul;14:1965-75). This amino acid position is well 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 alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002482847 SCV002785915 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 2021-10-12 criteria provided, single submitter clinical testing
OMIM RCV000009576 SCV000029794 pathogenic Tetralogy of Fallot 2005-07-15 no assertion criteria provided literature only

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