ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057136 SCV000279221 pathogenic not provided 2019-09-27 criteria provided, single submitter clinical testing Published functional studies in an animal model indicate that the N98S substitution results in a significant reduction in the number of neurofilaments, reduced axonal diameters, and in distal axon loss in the peripheral nervous system (Adebola et al., 2015; Zhao et al., 2017; Lancaster et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19158810, 26645395, 28501821, 20301384, 31827005, 27206872, 27863451, 28238949, 12566280, 21840889, 12477167, 25448007, 25552649, 28654681, 29293505, 29940160, 27458838, 30373780, 31211173, 33144682, 32907636, 32399692, 32376792)
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000057136 SCV001245758 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000857201 SCV001337494 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000034136 SCV001368210 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1f 2016-01-01 criteria provided, single submitter clinical testing This variant was 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
Genesis Genome Database RCV000857201 SCV000999783 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001027680 SCV001190244 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1f; Charcot-Marie-Tooth disease type 2E; Charcot-Marie-Tooth disease, dominant intermediate G 2019-05-15 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000034136 SCV001429941 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1f 2020-03-05 no assertion criteria provided clinical testing

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