ClinVar

Description

The p.P8R variant (also known as c.23C>G), located in coding exon 1 of the NEFL gene, results from a C to G substitution at nucleotide position 23. The proline at codon 8 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This alteration has been reported in the heterozygous form in multiple affected individuals with Charcot-Marie-Tooth (CMT) disease, and was reported to occur de novo in one affected individual (Jordanova A et al. Brain, 2003 Mar;126:590-7; Miltenberger-Miltenyi G et al. Arch Neurol, 2007 Jul;64:966-70; Lin KP et al. PLoS One, 2011 Dec;6:e29393; Horga A et al. J Neurol Neurosurg Psychiatry, 2017 07;88:575-585). Functional studies have shown that this alteration has an effect on intermediate filament formation, resulting in mitochondrial and axonal abnormalities (Zhai J et al. Hum Mol Genet, 2007 Dec;16:3103-16; Tradewell ML et al. J Neuropathol Exp Neurol, 2009 Jun;68:642-52). The NEFL c.22_23delCCinsAG alteration, which results in an identical amino acid change, has been reported to segregate with disease in a family displaying autosomal dominant inheritance of CMT (De Jonghe P et al. Ann Neurol, 2001 Feb;49:245-9). Based on the supporting evidence, this variant is likely to be causative of autosomal dominant CMT, type 1F/2E; however, its clinical significance for autosomal recessive CMT, type 1F/2E is unclear.