Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002351608 | SCV002650151 | uncertain significance | Cardiovascular phenotype | 2022-09-27 | criteria provided, single submitter | clinical testing | The p.K183N variant (also known as c.549G>C), located in coding exon 2 of the NKX2-5 gene, results from a G to C substitution at nucleotide position 549. The lysine at codon 183 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a non-compaction cardiomyopathy cohort; however, clinical details were limited (van Waning JI et al. J Am Heart Assoc, 2019 12;8:e012993). 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 alteration remains unclear. |
| Labcorp Genetics |
RCV003619774 | SCV004411207 | uncertain significance | Atrial septal defect 7 | 2023-11-01 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 183 of the NKX2-5 protein (p.Lys183Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NKX2-5-related conditions (PMID: 28330612). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1747918). 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. |