Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000621713 | SCV000737712 | uncertain significance | Cardiovascular phenotype | 2016-09-19 | criteria provided, single submitter | clinical testing | The p.E203G variant (also known as c.608A>G), located in coding exon 2 of the NKX2-5 gene, results from an A to G substitution at nucleotide position 608. The glutamic acid at codon 203 is replaced by glycine, an amino acid with some similar properties. This alteration has been previously reported in subjects with congenital heart disease (Hamanoue H et al. Cardiol Young, 2009 Sep;19:482-5; Dinesh SM et al. Genet Test Mol Biomarkers, 2010 Dec;14:873-9). Based on data from ExAC, the G allele has an overall frequency of <0.01% (4/71849). 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. |
| Labcorp Genetics |
RCV001240727 | SCV001413696 | uncertain significance | Atrial septal defect 7 | 2023-09-06 | criteria provided, single submitter | clinical testing | 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. This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 203 of the NKX2-5 protein (p.Glu203Gly). This variant is present in population databases (rs771533553, gnomAD 0.03%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 19678963, 21091212). ClinVar contains an entry for this variant (Variation ID: 519328). 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. |
| Prevention |
RCV004754506 | SCV005344746 | uncertain significance | NKX2-5-related disorder | 2024-07-03 | no assertion criteria provided | clinical testing | The NKX2-5 c.608A>G variant is predicted to result in the amino acid substitution p.Glu203Gly. This variant has been reported in an individual with ventricular septal defect (Dinesh et al. 2010. PubMed ID: 21091212) and reported in individuals with atrial septal defects (Hamanoue et al. 2009. PubMed ID: 19678963). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |