ClinVar Miner

Submissions for variant NM_006158.4(NEFL):c.1186G>A (p.Glu396Lys) (rs62636503)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057113 SCV000330708 pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing A pathogenic variant has been identified in the NEFL gene. The E396K variant has been previously reported to segregated with CMT in many families (Zuchner et al., 2004; Elbracht et al., 2014; Berciano et al., 2015) and the E396 residue has been identified as a mutation hotspot (Lin et al., 2011). Additionally, mice expressing the pathogenic variant (refered to as E397K using alternative nomenclature) had a phenotype consistent with CMT2E (Shen et al., 2011). It was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E396K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, E396K is interpreted to be a pathogenic variant.
Invitae RCV000534161 SCV000639652 pathogenic Charcot-Marie-Tooth disease type 2E 2019-04-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 396 of the NEFL protein (p.Glu396Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the heterozygous state in several individuals affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) (PMID: 27549087, 22206013, 19158810) and has been reported to segregate with disease in multiple families (PMID: 14733962, 24887401, 25877835, 17052987, 26109717). This variant is also known as p.Glu397Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 66671). Experimental studies have shown that transgenic mice carrying this missense recapitulate many aspects of the CMT type 2E phenotype (PMID: 21493625, 22288874). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001174356 SCV001337492 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057113 SCV000088226 not provided not provided no assertion provided not provided
OMIM RCV000585797 SCV000693720 pathogenic Charcot-Marie-Tooth disease, dominant intermediate G 2014-09-01 no assertion criteria provided literature only

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