ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1112C>T (p.Pro371Leu) (rs200067011)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041157 SCV000064848 uncertain significance not specified 2012-02-13 criteria provided, single submitter clinical testing The Pro371Leu variant (NEXN) has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is need ed to fully assess the clinical significance of the Pro371Leu variant.
GeneDx RCV000766516 SCV000236128 uncertain significance not provided 2013-02-06 criteria provided, single submitter clinical testing p.Pro371Leu (CCG>CTG): c.1112 C>T in exon 10 of the NEXN gene (NM_144573.3). The Pro371Leu variant in the NEXN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro371Leu results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Pro371Leu is damaging to the protein structure/function. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy. The 1,000 Genomes Project identified the Pro371Leu variant with a frequency of 0.1%, 1/757 alleles, in individuals of European ancestry. With the clinical and molecular information available at this time, we cannot definitively determine if Pro371Leu is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Blueprint Genetics RCV000183659 SCV000264125 uncertain significance Cardiomyopathy 2015-07-02 criteria provided, single submitter clinical testing
Invitae RCV000471176 SCV000549231 uncertain significance Dilated cardiomyopathy 1CC; Familial hypertrophic cardiomyopathy 20 2020-04-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 371 of the NEXN protein (p.Pro371Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs200067011, ExAC 0.01%) but has not been reported in the literature in individuals with a NEXN-related disease. ClinVar contains an entry for this variant (Variation ID: 47887). 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: Probably Damaging; Align-GVGD: Class C0). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253104 SCV001428636 uncertain significance Familial hypertrophic cardiomyopathy 20 2018-03-29 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000766516 SCV001741985 uncertain significance not provided no assertion criteria provided clinical testing

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