ClinVar Miner

Submissions for variant NM_006158.4(NEFL):c.995A>C (p.Gln332Pro) (rs59443585)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000015072 SCV000553805 pathogenic Charcot-Marie-Tooth disease type 2E 2016-11-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 332 of the NEFL protein (p.Gln332Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with in a single family affected with Charcot-Marie-Tooth type 2 (CMT2) (PMID: 10841809) and reported in an individual affected with CMT (PMID: 27088055). This variant is also known as (c.998A>C; p.Q333P) in the literature. ClinVar contains an entry for this variant (Variation ID: 14028). Experimental studies have shown that this missense change behaved like NFL gene knockout, reducing the fusion rate, decreasing length, and enhancing motility, subsequently impaired mitochondrial transport, and NEFL Q333P caused reversible misfolding of protein and could be refolded to form coil-coiled dimers in vitro using chaotropic agent (PMID: 22155564, 23618875). In addition, motor neurons microinjected with human Q333P mutant NFL cDNAs showed fragmentation of neurites and loss of targeted motor neurons (PMID: 17881652). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015072 SCV000035328 pathogenic Charcot-Marie-Tooth disease type 2E 2007-12-15 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057151 SCV000088264 not provided not provided no assertion provided not provided

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