ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1471G>C (p.Glu491Gln) (rs373057251)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183664 SCV000236133 uncertain significance not provided 2013-11-11 criteria provided, single submitter clinical testing p.Glu491Gln (GAG>CAG): c.1471 G>C in exon 11 of the NEXN gene (NM_144573.3). The Glu491Gln variant in the NEXN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu491Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid residue with a neutral, polar Glutamine residue at a position that is conserved across species. In silico analysis predicts Glu491Gln is probably damaging to the protein structure/function. The Glu491Gln variant was not observed with any significant frequency in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, no mutations affecting nearby residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Glu491Gln is a disease-causing mutation or a rare benign variant. The variant is found in DCM,DCM-CRDM panel(s).
Invitae RCV000647280 SCV000769069 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 491 of the NEXN protein (p.Glu491Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs373057251, ExAC 0.005%). This variant has not been reported in the literature in individuals with NEXN-related disease. ClinVar contains an entry for this variant (Variation ID: 201926). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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