Submissions for variant NM_144573.4(NEXN):c.995A>C (p.Glu332Ala)

gnomAD frequency: 0.00262  dbSNP: rs201763096

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2024-01-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000041187	SCV000339207	benign	not specified	2016-02-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528784	SCV000604454	benign	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618713	SCV000735346	benign	Cardiovascular phenotype	2016-06-15	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769821	SCV000901247	benign	Cardiomyopathy	2019-05-22	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV001781365	SCV000995287	benign	Premature ventricular contraction	2019-03-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000231450	SCV002799091	benign	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-07-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001528784	SCV004009856	benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	NEXN: BP4, BS1, BS2
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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528784	SCV001741133	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000041187	SCV001923524	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000041187	SCV001931161	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000041187	SCV001959782	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528784	SCV001973152	likely benign	not provided		no assertion criteria provided	clinical testing