ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1595T>C (p.Ile532Thr) (rs754656961)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183685 SCV000236154 uncertain significance not provided 2014-11-10 criteria provided, single submitter clinical testing The I532T variant has not been published as a mutation or as a benign polymorphism to our knowledge. The I532T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the I532T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is completely conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant is found in CARDIOMYOPATHY panel(s).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256888 SCV001433385 uncertain significance Familial hypertrophic cardiomyopathy 1 2020-03-20 criteria provided, single submitter clinical testing
Invitae RCV001360627 SCV001556553 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2020-08-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 532 of the NEXN protein (p.Ile532Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs754656961, ExAC 0.01%). This variant has not been reported in the literature in individuals with NEXN-related conditions. ClinVar contains an entry for this variant (Variation ID: 201943). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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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