ClinVar Miner

Submissions for variant NM_006158.5(NEFL):c.1315T>A (p.Phe439Ile)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001159512 SCV001321230 likely benign Charcot-Marie-Tooth disease, demyelinating, type 1f 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae RCV001207087 SCV001378426 uncertain significance Charcot-Marie-Tooth disease type 2E 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 439 of the NEFL protein (p.Phe439Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is present in population databases (rs199775873, ExAC 0.1%). This variant has been observed in the heterozygous state in individuals affected with Charcot-Marie-Tooth disease (PMID: 24078732, 28501821). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Not Available; Align-GVGD: Class C1). 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. 5

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