ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.836G>A (p.Arg279His)

gnomAD frequency: 0.00004  dbSNP: rs750349053
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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, 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, Molecular Genetics and Genomics, 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.

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