ClinVar Miner

Submissions for variant NM_006393.3(NEBL):c.1540G>T (p.Ala514Ser)

gnomAD frequency: 0.00008  dbSNP: rs781572930
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183634 SCV000236103 uncertain significance not provided 2014-11-03 criteria provided, single submitter clinical testing p.Ala514Ser (GCA>TCA): c.1540 G>T in exon 15 of the NEBL gene (NM_006393.2). A variant of unknown significance has been identified in the NEBL gene. The A514S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A514S variant was not observed in approximately 6,500 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 A514S 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 across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate 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).
Labcorp Genetics (formerly Invitae), Labcorp RCV001055022 SCV001219386 uncertain significance Primary dilated cardiomyopathy 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 514 of the NEBL protein (p.Ala514Ser). This variant is present in population databases (rs781572930, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 201908). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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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