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Cardiomyopathy_Paediatric

Gene: NEBL

Red List (low evidence)

NEBL (nebulette)
EnsemblGeneIds (GRCh38): ENSG00000078114
EnsemblGeneIds (GRCh37): ENSG00000078114
OMIM: 605491, Gene2Phenotype
NEBL is in 6 panels

2 reviews

Bryony Thompson (Royal Melbourne Hospital)

Comment on list classification: Limited gene-disease vailidity, Classification - 09/25/2020 by ClinGen Dilated Cardiomyopathy GCEP. Evidence Summary: NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of NEBL and autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7
Created: 18 Nov 2021, 2:04 a.m. | Last Modified: 18 Nov 2021, 2:04 a.m.
Panel Version: 0.158

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

7 individuals from 6 unrelated families described with missense variants in this gene; some with HOCM, some with DCM.
Sources: Literature
Created: 14 Apr 2020, 2:05 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypertrophic cardiomyopathy; dilated cardiomyopathy

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • South West GLH
  • Expert Review Red
  • NHS GMS
  • Literature
OMIM
605491
Clinvar variants
Variants in NEBL
Penetrance
None
Panels with this gene

History Filter Activity

28 Jul 2020, Gel status: 1

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: NEBL was added gene: NEBL was added to Cardiomyopathy_Paediatric. Sources: NHS GMS,Expert Review Red,South West GLH Mode of inheritance for gene: NEBL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted