Submissions for variant NM_144573.3(NEXN):c.1271C>T (p.Thr424Ile) (rs200442502)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183662	SCV000236131	uncertain significance	not provided	2013-07-12	criteria provided, single submitter	clinical testing	The Thr424Ile variant in the NEXN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Thr424Ile results in a non-conservative amino acid substitution of a neutral, polar Threonine with a non-polar Isoleucine, this substitution occurs at a position that is not well conserved across species. In silico analysis predicts Thr424Ile is benign to the protein structure/function. Additionally, very few missense mutations in the NEXN gene have been reported, and none of these reported mutations are near Thr424Ile, indicating this region of the protein may tolerate change. However, Thr424Ile was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Thr424Ile is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae	RCV000529099	SCV000648475	uncertain significance	Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20	2019-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 424 of the NEXN protein (p.Thr424Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs200442502, ExAC 0.002%). This variant has not been reported in the literature in individuals with a NEXN-related disease. ClinVar contains an entry for this variant (Variation ID: 201924). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NEXN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV001170728	SCV001333331	uncertain significance	Cardiomyopathy	2019-04-11	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV001256887	SCV001433384	uncertain significance	Dilated cardiomyopathy 1A	2020-01-31	criteria provided, single submitter	clinical testing