ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1401AGA[2] (p.Glu470del) (rs397517846)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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,; 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 2018-06-08 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 amino acid position is highly conserved in available vertebrate species. 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 (Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000701648 SCV000830459 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2020-10-01 criteria provided, single submitter clinical testing This variant, c.1407_1409delAGA, results in the deletion of 1 amino acid of the NEXN protein (p.Glu470del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762929322, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 47890). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid 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
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491718 SCV000298157 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2016-05-01 no assertion criteria provided clinical testing
GeneDx RCV001256889 SCV001790626 uncertain significance not provided 2020-11-19 no assertion criteria provided clinical testing Reported in association with DCM (Pugh et al., 2014; Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance by several clinical laboratories; one laboratory reported this variant in an adult with HCM who carried a pathogenic variant in another gene that was sufficient to explain the disease (SCV000064851.5; ClinVar Variant ID# 47890; Landrum et al., 2016); In-frame deletion of a single glutamic acid residue; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257)

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