Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000689746 | SCV000817412 | uncertain significance | Primary dilated cardiomyopathy | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg179*) in the NEBL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEBL cause disease. This variant is present in population databases (rs370153729, gnomAD 0.01%). 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: 569179). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Agnes Ginges Centre for Molecular Cardiology, |
RCV000999605 | SCV001156309 | uncertain significance | Hypertrophic cardiomyopathy; Aborted sudden cardiac death | 2018-10-15 | criteria provided, single submitter | research | NEBL Arg179Ter has been previously reported in heterozygous form in a patient presenting with fatigue, attributed to atrial flutter, left bundle branch block, enlarged LV and reduced ejection fraction (Arbustini et al., 2018), and homozygous form in an infant with pulmonary hypertension and LV dysfunction (Scott et al., 2018). We identified this heterozygous variant in 2 probands of Maori descent; 1 with HCM and 1 out of hospital cardiac arrest. NEBL Arg179Ter is present in the Genome Aggregation Database (MAF= 0.000022, http://gnomad.broadinstitute.org/), however Oceanian/Polynesian ethnicity's are not well represented. As a result we classify NEBL Arg179Ter as a variant of 'uncertain significance'. |
| Victorian Clinical Genetics Services, |
RCV002272332 | SCV002557388 | uncertain significance | Hypertrophic cardiomyopathy | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function is an unlikely mechanism of disease, as null mouse models have normal cardiac function (PMID: 25987543). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0710 – Other NMD predicted variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as VUS in ClinVar. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |