Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000154789 | SCV000204469 | uncertain significance | not specified | 2014-06-27 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The Val800Ile varia nt in NEBL has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/4406 of African American chromosomes by the NHLBI E xome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs367986765). Computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein and lizard and prairie vole both carry an isoleuci ne (Ile) at this position, raising the possibility that this change may be toler ated. In summary, while the clinical significance of the Val1800Ile variant is u ncertain, these data suggest that it is more likely to be benign. |
| Invitae | RCV000685453 | SCV000812935 | uncertain significance | Primary dilated cardiomyopathy | 2023-06-09 | 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 178094). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. This variant is present in population databases (rs367986765, gnomAD 0.02%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 800 of the NEBL protein (p.Val800Ile). |
| Ambry Genetics | RCV000154789 | SCV002738495 | uncertain significance | not specified | 2023-04-28 | criteria provided, single submitter | clinical testing | The c.2398G>A (p.V800I) alteration is located in exon 24 (coding exon 24) of the NEBL gene. This alteration results from a G to A substitution at nucleotide position 2398, causing the valine (V) at amino acid position 800 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Victorian Clinical Genetics Services, |
RCV000685453 | SCV002766685 | uncertain significance | Primary dilated cardiomyopathy | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. 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) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (12 heterozygotes, 1 homozygote). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated nebulin 23 repeat (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has been reported as a variant of uncertain significance (VUS) (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 |