ClinVar Genomic variation as it relates to human health

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.

The c.1407_1409delAGA (p.E470del) alteration is located in exon 11 (coding exon 10) of the NEXN gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.1407 and c.1409, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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.

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)

Variant summary: NEXN c.1407_1409delAGA (p.Glu470del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00012 in 1606714 control chromosomes, predominantly at a frequency of ~0.0003 within the African or African-American- and South Asian subpopulations in the gnomAD database (v4.0 dataset), including 1 homozygote. The observed variant frequency within African and South Asian control individuals in the gnomAD database is approximately 20-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEXN causing Dilated Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. c.1407_1409delAGA has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Pugh_2014, Walsh_2017, Pena-Pena_2021), however without providing strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 27532257, 32826072). ClinVar contains an entry for this variant (Variation ID: 47890). Based on the evidence outlined above, the variant was classified as likely benign.

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.