Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001221258 | SCV001393289 | uncertain significance | Charcot-Marie-Tooth disease type 2E | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 520 of the NEFL protein (p.Thr520Ile). This variant is present in population databases (rs750697495, gnomAD 0.03%). 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: 949731). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NEFL protein function. 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 | RCV002402674 | SCV002704935 | uncertain significance | Inborn genetic diseases | 2021-02-26 | criteria provided, single submitter | clinical testing | The p.T520I variant (also known as c.1559C>T), located in coding exon 4 of the NEFL gene, results from a C to T substitution at nucleotide position 1559. The threonine at codon 520 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Charcot Marie Tooth disease; however, its contribution to the development of autosomal recessive Charcot Marie Tooth disease is uncertain. |