Submissions for variant NM_006393.3(NEBL):c.2080C>T (p.Arg694Trp)

gnomAD frequency: 0.00064  dbSNP: rs114875104

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038696	SCV000062374	uncertain significance	not specified	2013-01-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg694Trp varia nt in NEBL has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.16% (7/4406) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs114875104). This frequency is too l ow to rule out a role in disease. Arginine (Arg) at position 694 is not conserve d in evolution, suggesting that a change to this position may be tolerated. This variant is less likely disease causing but additional studies are needed to ful ly assess its clinical significance.
GeneDx	RCV000766595	SCV000518848	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NEBL gene. The R694W variant has not been published as a pathogenic variant or reported as a benign variant, to our knowledge. The NHLBI Exome Sequencing Project, Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project reports R694W was observed in 0.1-0.2% of individuals of African background, indicating it may be a rare (benign) variant in this population. This substitution occurs at a position that is not conserved across species. Nevertheless, the R694W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088676	SCV000749732	likely benign	Primary dilated cardiomyopathy	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000038696	SCV003676528	uncertain significance	not specified	2021-09-01	criteria provided, single submitter	clinical testing	The c.2080C>T (p.R694W) alteration is located in exon 21 (coding exon 21) of the NEBL gene. This alteration results from a C to T substitution at nucleotide position 2080, causing the arginine (R) at amino acid position 694 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000766595	SCV003924133	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing	NEBL NM_006393.2 exon 25 p.Arg694Trp (c.2080C>T): This variant has not been reported in the literature and is present in 0.1% (38/24960) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-21106597-G-A). This variant is present in ClinVar (Variation ID:45491). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003924933	SCV004743964	likely benign	NEBL-related disorder	2022-08-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).