Submissions for variant NM_144573.4(NEXN):c.586C>T (p.Arg196Cys)

gnomAD frequency: 0.00007  dbSNP: rs369486891

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155781	SCV000205492	uncertain significance	not specified	2013-06-12	criteria provided, single submitter	clinical testing	The Arg196Cys in NEXN has not been reported in individuals with cardiomyopathy, but has been identified in 1/8146 European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino ac id is not well conserved in evolution, raising the possibility that a change wou ld be tolerated. Other computational analyses (biochemical amino acid propertie s, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the c linical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647286	SCV000769075	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 196 of the NEXN protein (p.Arg196Cys). This variant is present in population databases (rs369486891, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28333919, 31983221). ClinVar contains an entry for this variant (Variation ID: 179003). 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 NEXN 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768803	SCV000900175	uncertain significance	Cardiomyopathy	2022-07-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001582631	SCV001812851	uncertain significance	not provided	2025-02-19	criteria provided, single submitter	clinical testing	Has been reported in individuals with dilated cardiomyopathy (DCM) (PMID: 31983221, 36277766); Reported in a patient with cardiomyopathy and atrial fibrillation who experienced sudden cardiac death, however, this patient also harbored a potentially disease-causing variant in the LMNA gene (PMID: 28333919); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30354306, 36277766, 31983221, 28333919)
Molecular Genetics, Royal Melbourne Hospital	RCV002221204	SCV002498604	uncertain significance	Primary dilated cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in NEXN is predicted to replace arginine with cysteine at codon 196, p.(Arg196Cys). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in a coiled-coil region. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in gnomAD v2.1 is 0.02% (24/128,070 alleles) in the European (non-Finnish) population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 4.9, 95% CI 1.2-20.7) (cases - PMID: 31983221; controls - European non-TOPMED gnomAD v2.1). This variant has been observed in at least two patients with an alternate molecular basis for disease, a long QT syndrome case with a de novo CALM2 variant and a dilated cardiomyopathy case with a pathogenic LMNA variant (PMID: 28333919, 30354306). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS4_Moderate, BP5.
Ambry Genetics	RCV002354374	SCV002652674	uncertain significance	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	The p.R196C variant (also known as c.586C>T), located in coding exon 6 of the NEXN gene, results from a C to T substitution at nucleotide position 586. The arginine at codon 196 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (described as p.R132C) has been reported in a sudden unexplained death case who had dilated cardiomyopathy, atrial fibrillation, and additional cardiac variants detected; this variant was not detected in his affected mother (Bagnall RD et al. Genet. Med., 2017 10;19:1127-1133). This variant was also detected in an individual with prolonged QTc and hypertrophic cardiomyopathy, who also had a reportedly de novo CALM2 variant and additional cardiac variants also detected (Zahavich L et al. Circ Genom Precis Med, 2018 10;11:e002255). This variant has also been reported in a dilated cardiomyopathy (DCM) cohort (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV000647286	SCV002814571	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-08-19	criteria provided, single submitter	clinical testing