ClinVar Miner

Submissions for variant NM_006393.3(NEBL):c.82-4A>G

gnomAD frequency: 0.00021  dbSNP: rs368268112
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000151549 SCV000199684 likely benign not specified 2015-06-30 criteria provided, single submitter clinical testing c.82-4A>G in intron 1 of NEBL: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It ha s been identified in 25/66724 European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368268112).
GeneDx RCV001719938 SCV000236087 uncertain significance not provided 2022-12-21 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)
Invitae RCV000462811 SCV000563547 likely benign Primary dilated cardiomyopathy 2024-01-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619343 SCV000739893 uncertain significance Cardiovascular phenotype 2013-11-14 criteria provided, single submitter clinical testing The c.82-4A>G variant is located in the NEBL gene. This alteration results from an A to G substitution 4 nucleotides before coding exon 2. ​Based on data from the NHLBI Exome Sequencing Project (ESP), the G-allele has an overall frequency of approximately 0.05% (6/13006),havingnot been observed in 4406 of African American alleles, but observed in 0.07% (6/8600) of European American alleles. This variant was not found in the following population databases: dbSNP database or the 1000 Genomes Project.This nucleotide position is poorly conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native acceptor splice site; however, direct evidence is unavailable.Since supporting evidence is limited at this time, the clinical significance ofc.82-4A>Gremains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000151549 SCV000280398 uncertain significance not specified 2014-07-09 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS1-4 A>G (c.82-4 A>G) in NEBL (NM_006393.2) Given weak gene-disease association and the lack of available data on the specific variant we consider this variant a variant of uncertain significance. NEBL encodes nebulette, which aligns thin filaments and connects them with the myocardial Z-disk. It is a cardiac-specific member of the nebulin protein family, which all have "nebulin-repeats" that bind a single actin subunit and are involved in tropomyosin-troponin assembly. Arimura et al 200 sequenced NEBL in patients with DCM using a candidate gene approach and noted that one common variant, p.Asn654Lys, was more frequently seen in the homozygote state in patients with sporadic (but not familial) DCM than in controls. NEBL was one of 20 candidate genes analyzed in 260 DCM patients from the pediatric cardiomyopathy registry (Purevjav et al 2010). They found four missense variants in their patients which were absent in 300 controls, however three of these are in the ESP dataset and for the fourth there is another variant at the same codon present in ESP. Segregation data was not provided. They did construct transgenic mouse models that did show a cardiomyopathy phenotype. At least one of the patients also had endocardial fibroelastosis. I could find no studies reporting on linkage, segregation, or increased burden of rare NEBL variants in cardiomyopathy patients as compared to controls. I could find no reports of this specific variant in association with disease. The variant is not listed in ClinVar (as of July 9th, 2014). The variant was reported online in 6 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of July 9th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant is in dbSNP (rs368268112), pointing to the ESP data.

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