Submissions for variant NM_006393.3(NEBL):c.258+1G>A

gnomAD frequency: 0.00016  dbSNP: rs139581346

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222221	SCV000272201	likely benign	not specified	2019-12-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628809	SCV000749716	uncertain significance	Primary dilated cardiomyopathy	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the NEBL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), 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 (rs139581346, gnomAD 0.05%). 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: 229045). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222221	SCV005423042	uncertain significance	not specified	2024-10-07	criteria provided, single submitter	clinical testing	Variant summary: NEBL c.258+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing, however current evidence is not sufficient to establish loss of function as a mechanism for disease. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site, and one predicts the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.5e-05 in 1582410 control chromosomes (i.e. in 39 carriers) in the gnomAD database (v4.1 dataset). The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEBL causing Dilated Cardiomyopathy phenotype (7.8e-06). Although the allele frequency suggests that the variant is not causal for a severe, early onset, high penetrance, dominant disease phenotype, however the association with recessive conditions (or risk associations) cannot be excluded. To our knowledge, no occurrence of c.258+1G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 229045). Based on the evidence outlined above, the variant was classified as uncertain significance.