ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.995A>C (p.Glu332Ala) (rs201763096)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000041187 SCV000064878 benign not specified 2015-04-08 criteria provided, single submitter clinical testing p.Glu332Ala in exon 9 of NEXN: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (207/16506) of South Asian chro mosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs201763096).
GeneDx RCV000041187 SCV000236123 benign not specified 2016-11-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000231450 SCV000291374 benign not provided 2019-02-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000041187 SCV000339207 benign not specified 2016-02-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000311586 SCV000358981 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000368643 SCV000358982 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000041187 SCV000604454 benign not specified 2017-02-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618713 SCV000735346 benign Cardiovascular phenotype 2016-06-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769821 SCV000901247 likely benign Cardiomyopathy 2017-07-21 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852585 SCV000995287 benign Premature ventricular contraction 2019-03-25 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000041187 SCV000280402 uncertain significance not specified 2013-08-01 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu332Ala (c.995 A>C) in the NEXN gene. This variant is reviewed in detail below. Recently, missense mutations that cause defective interaction between nexilin and alpha-actin have been described in HCM. Nexilin (NEXN) is a cardiac Z-disc protein that has a crucial function to protect cardiac Z-discs from forces generated within the sarcomere. The Z-disc complex is located at either end of the contractile unit of the striated muscle and links titin and actin filaments from opposing sarcomere halves in a lattice connected by ?-actinin. The Z-discs provide a backbone for the insertions of actin-based thin filaments and represent a key interface between the contractile apparatus and the cytoskeleton. In addition, the complex molecular network of Z-disc proteins is pivotal for reception, transduction, and transmission of mechanical and biochemical signals Hassel et al. (2009) found that nexilin is highly abundant in the heart and skeletal muscle and is located specifically to the Z-disc; loss of nexilin in zebrafish led to perturbed Z-disc stability and heart failure. They identified one deletion and two missense mutations in NEXN in a large cohort of patients with dilated cardiomyopathy. Wang et al. (2010) Reported variants in NEXN to cause HCM. They screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease and identified two missense variants. The variant p. Glu332Ala has not been published in the literature. In silico analysis with PolyPhen-2 predicts the variant to be is benign. Analysis with Mutation Taster predicts it to be disease causing with a score of 2.92. The 332 at codon is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons. Gu332Ala results in a non-conservative amino acid substitution of a negtatively-charged Glutamic acid residue with a non-polar Alanine residue at a positive that is class conserved across species. In total the variant has been seen in 24/11896 published controls and individuals from publicly available population datasets. GeneDx did not provide laboratory control data. The NHLBI Exome Sequencing Project dataset identified this variant in 20/8186 alleles from individuals of European ancestry and 4/3710 alleles from individual of African American ancestry, which currently includes variant calls on ~6000 Caucasian and African American individuals (as of 5/15/13). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 5/15/13).

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