Submissions for variant NM_006393.3(NEBL):c.326T>C (p.Ile109Thr)

gnomAD frequency: 0.00006  dbSNP: rs371620771

Total submissions: 2

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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538786	SCV000623478	uncertain significance	Primary dilated cardiomyopathy	2023-08-10	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 201900). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. This variant is present in population databases (rs371620771, gnomAD 0.05%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 109 of the NEBL protein (p.Ile109Thr).