ClinVar Miner

Submissions for variant NM_006158.5(NEFL):c.270G>C (p.Glu90Asp)

gnomAD frequency: 0.00001  dbSNP: rs767370918
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000640666 SCV000762261 uncertain significance Charcot-Marie-Tooth disease type 2E 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 90 of the NEFL protein (p.Glu90Asp). This variant is present in population databases (rs767370918, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NEFL-related conditions. ClinVar contains an entry for this variant (Variation ID: 533516). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NEFL protein function with a positive predictive value of 80%. This variant disrupts the p.Glu90 amino acid residue in NEFL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12566280, 19158810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV002440281 SCV002745005 uncertain significance Inborn genetic diseases 2021-11-09 criteria provided, single submitter clinical testing The p.E90D variant (also known as c.270G>C), located in coding exon 1 of the NEFL gene, results from a G to C substitution at nucleotide position 270. The glutamic acid at codon 90 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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