ClinVar Miner

Submissions for variant NM_006393.3(NEBL):c.180G>C (p.Lys60Asn)

gnomAD frequency: 0.00382  dbSNP: rs41277374
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Total submissions: 8
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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 RCV000038691 SCV000062369 likely benign not specified 2015-05-20 criteria provided, single submitter clinical testing p.Lys60Asn in exon 3 of NEBL: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (423/66580) of European chromoso mes by the Exome Aggregation Consortium (ExAC,; d bSNP rs41277374).
GeneDx RCV000721100 SCV000236088 benign not provided 2020-09-04 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259)
Invitae RCV001079395 SCV000289521 benign Primary dilated cardiomyopathy 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620464 SCV000739888 uncertain significance Cardiovascular phenotype 2013-10-04 criteria provided, single submitter clinical testing The p.K60N variant (also known as c.180G>C) is located in coding exon 3 of theNEBLgene. This alteration results from a G to C substitution at nucleotide position 180. The lysine at codon 60 is replaced by asparagine, an amino acid with some similar properties. ​​In an initial publication associating NEBLwith dilated cardiomyopathy (DCM), this alteration was identified in a cohort of 260 individuals with DCM and absent in 600 control alleles. This alteration was found to be de novoin a proband with adult onset DCM. Authors subsequently developed a transgenic mouse model, and founder mice with this alteration developed severe heart failure at one year old. Embryos with this alteration did not survive, presenting the possibility of embryonic lethality with the p.K60N alteration(Purevjav E etal. J Am Coll Cardiol. 2010;56(18):1493-1502).However, a later publication denotes that the presence and frequency of this alteration in a large population based database from the Exome Sequencing Project (ESP) creates uncertainty regarding its pathogenicity (Andreasen C etal. Eur J Hum Genet. 2013;21(9):918-928). This variant was previously reported in dbSNP asrs41277374. Based on data from the NHLBI Exome Sequencing Project (ESP), the C-allele has an overall frequency of approximately0.52% (67/12998), having been observed in 0.71% (61/8594) of European American alleles, and in 0.14% (6/4404)of African American alleles studied. Based on data from the 1000 Genomes Project, the C-allele has an overall frequency of approximately0.18% (4/2184). The highest observed frequency was 1.12% (2/178) of Britishchromosomes studied. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence for this variant is conflicting and limited at this time, its clinical significance remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038691 SCV003928279 likely benign not specified 2023-04-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000721100 SCV004126537 benign not provided 2022-06-01 criteria provided, single submitter clinical testing NEBL: BS1, BS2
PreventionGenetics, part of Exact Sciences RCV003934927 SCV004749675 likely benign NEBL-related disorder 2019-03-27 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 RCV000721100 SCV000280395 likely benign not provided 2016-08-01 no assertion criteria provided provider interpretation Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes).

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