Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004025264 | SCV000741221 | uncertain significance | Cardiovascular phenotype | 2024-02-12 | criteria provided, single submitter | clinical testing | The c.890_891dupTC variant, located in coding exon 2 of the NKX2-5 gene, results from a duplication of TC at nucleotide position 890, causing a translational frameshift with a predicted alternate stop codon (p.G298Sfs*4). This alteration occurs at the 3' terminus of theNKX2-5 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 8% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001038060 | SCV001201504 | uncertain significance | Atrial septal defect 7 | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gly298Serfs*4) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the NKX2-5 protein. This variant is present in population databases (rs778545351, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NKX2-5-related conditions. ClinVar contains an entry for this variant (Variation ID: 520891). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193907 | SCV001363076 | uncertain significance | not specified | 2019-06-10 | criteria provided, single submitter | clinical testing | Variant summary: NKX2-5 c.890_891dupTC (p.Gly298SerfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250164 control chromosomes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease phenotype (5e-06), suggesting that the variant is benign. To our knowledge, no occurrence of c.890_891dupTC in individuals affected with Congenital Heart Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Due to the conflicting evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV002483744 | SCV002777952 | 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 | 2021-11-04 | criteria provided, single submitter | clinical testing |