ClinVar Miner

Submissions for variant NM_006158.4(NEFL):c.986T>C (p.Leu329Pro) (rs876661290)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762503 SCV000892828 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764773 SCV000895911 uncertain significance Charcot-Marie-Tooth disease, demyelinating, type 1f; Charcot-Marie-Tooth disease type 2E; CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000762503 SCV000280000 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEFL gene. The L329P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. The L329P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000535984 SCV000639669 uncertain significance Charcot-Marie-Tooth disease type 2E 2018-06-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 329 of the NEFL protein (p.Leu329Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an NEFL-related disease. ClinVar contains an entry for this variant (Variation ID: 234913). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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