ClinVar Miner

Submissions for variant NM_213569.2(NEBL):c.357+73532T>C (rs371620771)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183621 SCV000236090 uncertain significance not provided 2014-05-07 criteria provided, single submitter clinical testing p.Ile109Thr (ATT>ACT): c.326 T>C in exon 4 of the NEBL gene (NM_006393.2) Although rare, mutations in the NEBL gene have been reported in association with dilated cardiomyopathy (DCM) and endocardialfibroelastosis (Purevjav E at al., 2010). The I109T variant has not been published as a mutation or as a benign polymorphism to our knowledge. The I109T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. In addition, the I109T 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 completely conserved across species. Nevertheless, in silico analysis is inconsistent in its prediction, but at least two models concur that this variant likely does not alter the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with a NEBL-related disorder, 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. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000538786 SCV000623478 uncertain significance Primary dilated cardiomyopathy 2017-06-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 109 of the NEBL protein (p.Ile109Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs371620771, ExAC 0.04%). This variant has not been reported in the literature in individuals with a NEBL-related disease. ClinVar contains an entry for this variant (Variation ID: 201900). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NEBL function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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