Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000489995 | SCV000577142 | uncertain significance | not provided | 2017-12-11 | criteria provided, single submitter | clinical testing | The Q128R variant of uncertain significance in the NEBL gene has been reported previously in a newborn with DCM and endocardial fibroelastosis (Purevjav et al., 2010). The Q128R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In vivo studies in mice for the Q128R variant demonstrated possible embryonic lethality due to severe cardiac abnormalities (Purevjav et al., 2010). Nevertheless, additional functional studies are needed to further elucidate the effect of this variant on protein structure/function. The Q128R variant is observed in 5/66,694 alleles (0.01%) from individuals of non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014). |
| Labcorp Genetics |
RCV001865514 | SCV002112748 | uncertain significance | Primary dilated cardiomyopathy | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 128 of the NEBL protein (p.Gln128Arg). This variant is present in population databases (rs139809958, gnomAD 0.005%). This missense change has been observed in individual(s) with dilated cardiomyopathy and endocardial fibroelastosis (PMID: 20951326). ClinVar contains an entry for this variant (Variation ID: 426645). 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. Experimental studies have shown that this missense change affects NEBL function (PMID: 20951326). 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. |