ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.864G>T (p.Met288Ile) (rs371666396)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217251 SCV000272217 uncertain significance not specified 2015-04-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met288Ile variant in NEXN has not been reported in individuals with cardiomyopathy, but h as been identified in 1/65588 European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371666396). This variant i s located in the last base of the exon, which is part of the 5? splice region. C omputational tools do suggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. Although this variant is predi cted to disrupt splicing, the NEXN gene has not been widely studied and the spec trum of variants leading to disease is not well-defined. Loss of NEXN function h as been shown to cause DCM in zebrafish (Hassel 2009) and several predicted loss -of-function variants have been reported in individuals with a wide range of phe notypes including ASD, HCM, and DCM with LVNC, VT, and/or MVP (LMM unpublished d ata, Syrmou 2013, Pugh 2014); however, it remains unclear if one or both copies of the gene must be affected to cause disease (Hassel 2009, LMM unpublished data ). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Met288Ile variant is uncertain.

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