Submissions for variant NM_006393.3(NEBL):c.1108C>A (p.Gln370Lys)

gnomAD frequency: 0.00004  dbSNP: rs146198369

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154793	SCV000204473	uncertain significance	not specified	2013-12-12	criteria provided, single submitter	clinical testing	The Gln370Lys variant in NEBL has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs146198369). Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. Additional information is needed to fully assess the clinical signif icance of this variant.
Invitae	RCV001088431	SCV001014077	benign	Primary dilated cardiomyopathy	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000786387	SCV002008011	likely benign	not provided	2020-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000154793	SCV002738991	uncertain significance	not specified	2023-11-21	criteria provided, single submitter	clinical testing	The p.Q370K variant (also known as c.1108C>A), located in coding exon 11 of the NEBL gene, results from a C to A substitution at nucleotide position 1108. The glutamine at codon 370 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003945220	SCV004762180	likely benign	NEBL-related disorder	2022-05-10	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).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786387	SCV000925195	uncertain significance	not provided	2015-10-01	no assertion criteria provided	provider interpretation	Genetic testing comprehensive cardiomyopathy panel: The patient had genetic testing. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1). Results showed that a variant was found (see report below): -p.Gln370Lys (c.1108C>A) in the NEBL gene (NM_006393.2) This variant is reviewed in detail below. The labs this variant as a variant of unknown significance. Given lack of case data and it's presence in south Asian control populations we consider this a variant of unknown significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant hasn't been reported with disease previously although it has been reported in general population studies. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.99). The glutamine at codon 370 is not completely conserved across species, (cats have a histidine at that position). No other missense variants have been reported in clinvar in this region of the gene. There are 126 people with variation at codon 370 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent that were not selected for cardiovascular disease (as of October 5, 2015). The frequency in the South Asian population in this cohort is 1/70 people (118/8,254 ppl of South Asian descent). Therefore this is a common variation in the South Asian population with a frequency of >1% of the population. Genetic testing comprehensive arrhythmia panel: The patient had genetic testing at the GeneDx laboratory, using their comprehensive arrhythmia panel. The test included sequencing and duplication/deletion analysis of 30 genes associated with a variety of hereditary arrhythmias: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2 (HERG), KCNJ2, KCNJ5, KCNJ8, KCNQ1, NKX2.5, PKP2, RANGRF (MOG1), RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1,TMEM43 (See report below). Results reported on 8/13/2015 show that no disease-causing variants were found.