ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.520G>A (p.Val174Met)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002340780 SCV002642003 uncertain significance Cardiovascular phenotype 2022-03-25 criteria provided, single submitter clinical testing The p.V174M variant (also known as c.520G>A), located in coding exon 2 of the NKX2-5 gene, results from a G to A substitution at nucleotide position 520. The valine at codon 174 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV003619773 SCV004536745 uncertain significance Atrial septal defect 7 2023-06-17 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1746101). 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. This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 174 of the NKX2-5 protein (p.Val174Met).

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