ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1640T>C (p.Ile547Thr) (rs753636624)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618647 SCV000735489 uncertain significance Cardiovascular phenotype 2016-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000183686 SCV000236155 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing The I547T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I547T 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. The I547T 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. This substitution occurs at a position that is conserved when present 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. No missense mutations in nearby residues have been reported in association with cardiomyopathy, suggesting 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.
Invitae RCV000820361 SCV000961070 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 547 of the NEXN protein (p.Ile547Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs753636624, ExAC 0.02%). This variant has been observed in an individual with dilated cardiomyopathy, who also carried additional variants in LMNA, NEXN and TTN (PMID: 28333919). This variant is also known as p.Ile483Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 201944). 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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