ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.613G>A (p.Glu205Lys) (rs201447781)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041179 SCV000064870 uncertain significance not specified 2013-01-22 criteria provided, single submitter clinical testing The Glu205Lys variant in NEXN has not been reported in the literature, but has b een identified by our laboratory in 1 individual with HCM and in 1 infant with L VNC, hypotonia and motor delay who carried a likely pathogenic variant in anothe r gene. This variant has also been identified in 4/8168 European American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs201447781). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional informat ion is needed to fully assess the clinical significance of the Glu205Lys variant .
GeneDx RCV000766514 SCV000236152 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEXN gene. The E205K variant has been reported in two individuals with sudden cardiac arrest/death and non-specific cardiac disease; however, each individual also harbored other cardiogenetic variants (Mellor et al., 2017; Seidelmann et al., 2017). TheE205K variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members.The E205K variant is observed in 57/126,306 (0.04%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016). This substitution occurs at a position where amino acids with similar properties to glutamic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the E205K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000473581 SCV000549240 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 205 of the NEXN protein (p.Glu205Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201447781, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NEXN-related disease. ClinVar contains an entry for this variant (Variation ID: 47908). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769815 SCV000901241 uncertain significance Cardiomyopathy 2017-07-26 criteria provided, single submitter clinical testing

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