Submissions for variant NM_006393.3(NEBL):c.267C>G (p.Tyr89Ter)

gnomAD frequency: 0.00154  dbSNP: rs147622517

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154796	SCV000204476	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Tyr89X varian t in NEBL has been identified in 2 individuals with HCM and 1 individual with LV H (LMM data). It has also been identified in 0.24% (305/128294) of European chro mosomes by by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant l eads to a premature termination codon at position 89, which is predicted to lead to a truncated or absent protein; however, this variant does not occur in all t ranscripts of the gene. In addition, the association of variants in NEBL with ca rdiomyopathy has not been clearly established. In summary, while the clinical si gnificance of the p.Tyr89X variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.
GeneDx	RCV001528465	SCV000236089	likely benign	not provided	2021-09-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27662471)
Blueprint Genetics	RCV000208260	SCV000264121	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-11-02	criteria provided, single submitter	clinical testing
Invitae	RCV000232013	SCV000289528	likely benign	Primary dilated cardiomyopathy	2024-01-18	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000999618	SCV001156322	benign	Long QT syndrome; Hypertrophic cardiomyopathy; Sudden unexplained death	2018-06-12	criteria provided, single submitter	research	This variant has been identified in 4 probands with different clinical presentations (Long QT syndrome, hypertrophic cardiomyopathy, sudden unexplained death in epilepsy and sudden unxeplained death in a young person) which suggests that this variant is an incidental finding. Furthermore the variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00128, which is much higher then the frequency of any inherited cardiac condition, therefore we classify NEBL p.Tyr89Ter as 'benign'.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000232013	SCV002766659	likely benign	Primary dilated cardiomyopathy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely benign. 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 (PMID: 27186169). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript, which is the longest (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of dilated cardiomyopathy (gnomAD v3; 202 heterozygotes, 5 homozygotes). (SB) 0710 - Other NMD-predicted variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These variants have been reported mostly as VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been observed in several patients within cardiac disease cohorts, but has been classified as likely benign, benign and as a VUS (ClinVar, PMID: 27662471, PMID: 28750076). (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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154796	SCV004122400	benign	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: NEBL c.267C>G (p.Tyr89X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in NEBL as causative of disease. The variant allele was found at a frequency of 0.0013 in 249424 control chromosomes (gnomAD). The observed variant frequency is approximately 162-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEBL causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.267C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy and an individual with Restrictive Cardiomyopathy, both of whom had variants considered to be likely pathogenic/pathogenic reported in other cardiac-related genes, providing supporting evidence for a benign role (e.g. Kostareva_2016, Forleo_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28750076, 27662471, 33762593). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as benign/likely benign and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003927496	SCV004741581	likely benign	NEBL-related disorder	2022-01-16	criteria provided, single submitter	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).
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254748	SCV001430837	benign	Hypertrophic cardiomyopathy	2019-11-28	no assertion criteria provided	research	The NEBL Tyr89Ter variant if found at a high allele frequency in the the Genome Aggregation Database (MAF=0.0013; http://gnomad.broadinstitute.org/). We identified this variant in a female HCM patient, however the variant did not segregate to another affected family member. Based on high allele frequencies in the general population and our familial data, we classify NEBL Tyr89Ter as "benign".
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528465	SCV001740259	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528465	SCV001928047	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528465	SCV001967601	likely benign	not provided		no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute	RCV003982910	SCV004708197	uncertain significance	Distal monosomy 10p	2024-03-08	no assertion criteria provided	clinical testing