ClinVar Miner

Submissions for variant NM_006158.4(NEFL):c.293A>G (p.Asn98Ser) (rs58982919)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057136 SCV000279221 pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing The N98S pathogenic variant in the NEFL gene has been reported multiple times previously (as N97S in some publications due to alternative nomenclature) in association with CMT (Yoshihara et al., 2002; Jordanova et al., 2003; Abe et al., 2009; Baets et al., 2011; Berciano et al., 2015). The N98S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N98S variant is a conservative amino acid substitution. This substitution occurs at a position that is conserved across species. Functional analysis in a cell line derived from an individual harboring the N98S variant demonstrated reduced mitochondrial mobility in axons compared to age-matched controls, and abnormal accumulation of neurofilament proteins in the cell body likely due to abnormal trafficking of the protein (Saporta et al., 2015).
Invitae RCV000554079 SCV000639659 pathogenic Charcot-Marie-Tooth disease type 2E 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 98 of the NEFL protein (p.Asn98Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease (PMID: 19158810, 21840889, 25448007, 12477167, 27206872, 26645395). This variant has also been shown to arise de novo in one individual affected with Charcot-Marie-Tooth disease (PMID: 12566280). This variant is also known as p.Asn97Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 41236). Experimental studies in knock-in mice show that this missense substitution leads to NEFL protein aggregates in neurons and a decrease in neurofilament number and axon size (PMID: 25552649). In addition, cultured motor neurons derived from stem cells from an affected individual carrying this variant show cytoskeletal abnormalities (PMID: 25448007). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000034136 SCV000058067 pathologic Charcot-Marie-Tooth disease, demyelinating, type 1f 2012-10-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057136 SCV000088249 not provided not provided no assertion provided not provided
OMIM RCV000585792 SCV000693719 pathogenic CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G 2018-03-06 no assertion criteria provided literature only

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