ClinVar Miner

Submissions for variant NM_144573.3(NEXN):c.1935C>G (p.Phe645Leu) (rs794729086)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183673 SCV000236142 likely pathogenic not provided 2013-08-12 criteria provided, single submitter clinical testing p.Phe645Leu (TTC>TTG): c.1935 C>G in exon 13 of the NEXN gene (NM_144573.3). The Phe645Leu variant in the NEXN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Phe645Leu results in a semi-conservative amino acid substitution of a large, non-polar Phenylalanine residue with a non-polar Leucine residue at a position that is conserved across species. In silico analysis predicts Phe645Leu is probably damaging to the protein structure/function. A mutation in a nearby residue (Tyr652Cys) has been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, the Phe645Leu variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Phe645Leu is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223684 SCV000280401 uncertain significance not specified 2015-05-07 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. NEXN c.1935 C>G (p.Phe645Leu; F645L) Recently, missense mutations that cause defective interaction between nexilin and alpha-actin have been described in HCM. Nexilin (NEXN) is a cardiac Z-disc protein that has a crucial function to protect cardiac Z-discs from forces generated within the sarcomere. The Z-disc complex is located at either end of the contractile unit of the striated muscle and links titin and actin filaments from opposing sarcomere halves in a lattice connected by ?-actinin. The Z-discs provide a backbone for the insertions of actin-based thin filaments and represent a key interface between the contractile apparatus and the cytoskeleton. In addition, the complex molecular network of Z-disc proteins is pivotal for reception, transduction, and transmission of mechanical and biochemical signals Hassel et al. (2009) found that nexilin is highly abundant in the heart and skeletal muscle and is located specifically to the Z-disc; loss of nexilin in zebrafish led to perturbed Z-disc stability and heart failure. They identified one deletion and two missense mutations in NEXN in a large cohort of patients with dilated cardiomyopathy. Wang et al. (2010) Reported variants in NEXN to cause HCM. They screened NEXN in 121 unrelated HCM patients who did not carry any mutation in eight genes commonly mutated in myofilament disease and identified two missense variants. This variant is novel. Phe645Leu results in a semi-conservative amino acid substitution of a large, non-polar Phenylalanine residue with a non-polar Leucine residue. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation taster predicts this variant ot be disease-causing. The phenylalanine at codon 645 is conserved across species, as are neighboring amino acids. Another variant has been reported in association with disease at nearby codons (Tyr652Cys). This variant was published by Hassel et al. (2009) in association with dilated cardiomyopathy (see above for more discussion about Hassel's findings) In total the variant has not been seen in ~7,751 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 645 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/26/13). Note that this dataset does not match the patient's ancestry (Phillipines). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/26/13). The variant was not observed in the following laboratory and published control samples: GeneDx did not include any control data. Hassel et al. Reported no variants found in 1,251 "ethnically matched" healthy controls, although the ethnicity of the patient population is not clear.

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