Submissions for variant NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del)

dbSNP: rs397517846

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041160	SCV000064851	uncertain significance	not specified	2015-02-10	criteria provided, single submitter	clinical testing	The p.Glu470del variant in NEXN has been identified by our laboratory in 1 infan t with DCM, 1 adult with LVNC (Pugh 2014), and 1 adult with HCM who carried a pa thogenic variant in another gene that was sufficient to explain the disease. Thi s variant has also been identified in 4/16472 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3975 17846). This variant is a deletion of a single amino acid at position 470 and do es not alter the protein reading-frame. It is unclear if this deletion will impa ct protein function. In summary, the clinical significance of the p.Glu470del va riant is uncertain.
Center for Medical Genetics Ghent, University of Ghent	RCV000240639	SCV000299267	uncertain significance	Dilated cardiomyopathy 1CC	2016-02-09	criteria provided, single submitter	clinical testing	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server). The variant results in an inframe deletion of one amino acid and thus reduces the length of the protein.
Ambry Genetics	RCV000621584	SCV000739980	uncertain significance	Cardiovascular phenotype	2020-12-01	criteria provided, single submitter	clinical testing	The c.1407_1409delAGA variant (also known as p.E470del) is located in coding exon 10 of the NEXN gene. This variant results from an in-frame AGA deletion at nucleotide positions 1407 to 1409. This results in the in-frame deletion of a glutamic acid at codon 470. This variant was reported in 1 individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes and in one individual from a DCM genetic testing cohort; however, clinical details were limited, and reports may overlap (Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000701648	SCV000830459	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-10-03	criteria provided, single submitter	clinical testing	This variant, c.1407_1409del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Glu470del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762929322, gnomAD 0.02%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 47890). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256889	SCV001433386	uncertain significance	not provided	2020-05-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001256889	SCV001790626	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Identified in patients with DCM in the published literature (Pugh et al., 2014; Walsh et al., 2017); In-frame deletion of a single glutamic acid residue; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780)
Fulgent Genetics, Fulgent Genetics	RCV000701648	SCV002780369	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-11-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001256889	SCV003813616	uncertain significance	not provided	2019-07-15	criteria provided, single submitter	clinical testing
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491718	SCV000298157	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2016-05-01	no assertion criteria provided	clinical testing