Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000214249 | SCV000272216 | uncertain significance | not specified | 2015-02-12 | criteria provided, single submitter | clinical testing | The p.Arg279His variant in NEXN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/65886 of European chromosomes and 1/11492 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). Computational prediction tools and conservation an alysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg279His variant is uncertain. |
Fulgent Genetics, |
RCV002478770 | SCV002778704 | uncertain significance | Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 | 2021-10-22 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002478770 | SCV003295318 | uncertain significance | Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 | 2023-11-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 279 of the NEXN protein (p.Arg279His). This variant is present in population databases (rs750349053, gnomAD 0.009%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 229059). 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) performed at Invitae indicates that this missense variant is not expected to disrupt NEXN protein function with a negative predictive value of 80%. 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 | RCV003165544 | SCV003853693 | uncertain significance | Cardiovascular phenotype | 2022-11-05 | criteria provided, single submitter | clinical testing | The p.R279H variant (also known as c.836G>A), located in coding exon 7 of the NEXN gene, results from a G to A substitution at nucleotide position 836. The arginine at codon 279 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
ARUP Laboratories, |
RCV003736650 | SCV004563427 | uncertain significance | not provided | 2023-09-08 | criteria provided, single submitter | clinical testing | The NEXN c.836G>A; p.Arg279His variant (rs750349053) is reported in the literature in a cohort of individuals with sudden unexpected death, although its clinical significance was not demonstrated (Lin 2017). This variant is found in the general population with a low overall allele frequency of 0.002% (5/248,420 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.174). Given the lack of clinical and functional data, the significance of the p.Arg279His variant is uncertain at this time. References: Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119. |