ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1174C>T (p.Arg392Ter) (rs750076188)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000222720 SCV000272207 uncertain significance not specified 2015-04-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg392X v ariant in NEXN has not been previously reported in individuals with cardiomyopat hy, but has been identified in 1/64806 of European chromosomes by the Exome Aggr egation Consortium (ExAC, This nonsense variant leads to a premature termination codon at position 392, which is predicted to l ead to a truncated or absent protein. Although the severe nature of this change increases the likelihood that the variant is pathogenic, the NEXN gene has not b een widely studied and the spectrum of variants leading to disease is not well-d efined. Loss of NEXN function has been shown to cause DCM in zebrafish (Hassel 2 009, Wang 2010) and loss of function variants have been identified in individual s with a range of cardiomyopathies (LMM unpublished data); however, it remains u nclear if one or both copies of the gene need to be affected to cause disease. I n summary, while there is some suspicion for a pathogenic role, the clinical sig nificance of the p.Arg392X variant is uncertain.
Invitae RCV000820993 SCV000961732 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2018-10-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg392*) in the NEXN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs750076188, ExAC 0.002%). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 229051). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NEXN cause disease. 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196151 SCV001366672 uncertain significance Dilated cardiomyopathy 1CC 2019-05-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5.
Loeys Lab,Universiteit Antwerpen RCV001375648 SCV001572576 uncertain significance Hypertrophic cardiomyopathy 2021-02-26 criteria provided, single submitter clinical testing This sequence change results in a frameshift variant in the NEXN gene (p.(Arg392*)). This variant is present in population databases with a prevalence of 7/276332in GnomAD. Loss of function of NEXN caused DCM in zebrafish (PMID: 19881492). This variant has not been reported in the literature. We identified the variant in 3 unrelated patients: two patients with DCM and one patient with HCM. In the HCM family a second individual with HCM also carried the variant (limited data on segregation:PP1weak). No segregation data are available for the DCM families. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357462 SCV001552942 uncertain significance not provided no assertion criteria provided clinical testing The NEXN p.Arg392X variant was identified in a study performing NGS on 639 patients with dilated cardiomyopathy (Haas_2014_PMID:25163546). It was not identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs750076188) and Clinvar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 7 of 280056 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 6 of 128186 chromosomes (freq: 0.000047) and European (Finnish) in 1 of 25012 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Arg392X variant leads to a premature stop codon at position 392 which is predicted to lead to a truncated or absent protein and loss of function. The role of NEXN loss of function variants in disease is still unclear, however NEXN knock-out mice studies display a cardiomyopathy phenotype (Aherrahrou_2016_PMID:26659360). Further, MutationTaster predicts the variant to be disease-causing (prob: 1). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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