Submissions for variant NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)

dbSNP: rs58982919

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057136	SCV000279221	pathogenic	not provided	2023-03-20	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 (gnomAD); This variant is associated with the following publications: (PMID: 19158810, 26645395, 28501821, 20301384, 27206872, 27863451, 28238949, 12566280, 21840889, 12477167, 25448007, 25552649, 28654681, 29293505, 29940160, 27458838, 30373780, 32376792, 34232518, 31827005, 33144682, 32907636, 32399692, 31211173, 35872528)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554079	SCV000639659	pathogenic	Charcot-Marie-Tooth disease type 2E	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 98 of the NEFL protein (p.Asn98Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 12477167, 12566280, 19158810, 21840889, 25448007, 26645395, 27206872). In at least one individual the variant was observed to be de novo. This variant is also known as p.Asn97Ser. ClinVar contains an entry for this variant (Variation ID: 41236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NEFL protein function. Experimental studies have shown that this missense change affects NEFL function (PMID: 25448007, 25552649). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001027680	SCV001190244	pathogenic	Charcot-Marie-Tooth disease type 1F; Charcot-Marie-Tooth disease type 2E; Charcot-Marie-Tooth disease, dominant intermediate G	2019-05-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000057136	SCV001245758	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NEFL: PS2:Very Strong, PM2, PS3:Moderate, PS4:Moderate, PP1
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 type 1F	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000034136	SCV001429941	pathogenic	Charcot-Marie-Tooth disease type 1F	2021-09-28	criteria provided, single submitter	clinical testing
3billion	RCV000034136	SCV002012110	pathogenic	Charcot-Marie-Tooth disease type 1F	2024-03-07	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected individual (PMID:12566280, 26645395, 25552649, 32376792, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25552649, PS3). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novo (3billion dataset, PM6). A different missense change at the same codon (p.Glu545Lys) has been reported as pathogenic (VCV000013655.18 PM5). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.938, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001843465	SCV002102851	likely pathogenic	Sensorineural hearing loss disorder; Developmental disorder	2021-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000857201	SCV004101323	pathogenic	Charcot-Marie-Tooth disease	2023-08-14	criteria provided, single submitter	clinical testing	The NEFL c.293A>G (p.Asn98Ser) missense variant has been identified in at least eight unrelated individuals with a phenotype consistent with Charcot-Marie-Tooth disease, including in a de novo state (PMID: 35872528; 28501821; 21840889; 31211173; 30373780; 27206872). In one family, the variant segregated with the disease in the proband's affected son. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Motor neurons derived from patient induced pluripotent stem cells show abnormalities in cytoskeletal structure, mitochondrial trafficking, and electrophysiological properties (PMID: 25448007). A knock-in mouse model of the p.Asn98Ser variant also shows tremor as well as cellular features of neuropathy (PMID: 25448007). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.293A>G (p.Asn98Ser) variant is classified as pathogenic for Charcot-Marie-Tooth disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000857201	SCV004848847	pathogenic	Charcot-Marie-Tooth disease	2022-11-03	criteria provided, single submitter	clinical testing	The p.Asn98Ser variant in NEFL has been reported in several individuals affected with Charcot-Marie-Tooth disease, also as a de novo occurence (Abe 2009 PMID: 19158810, Baets 2011 PMID: 21840889, Saporta 2015 PMID: 25448007, Yoshihara 2002 PMID: 12477167, Yang 2016 PMID: 27206872, Jordanova 2003 PMID: 12566280, Berciano 2016 PMID: 26645395, Adebola 2015 PMID: 25552649, Volodarsky 2021 PMID: 32376792) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 41236). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Animal models in mice have shown that this variant causes Charcot-Marie-Tooth disease (Adebola 2015 PMID: 25552649, Saporta 2015 PMID: 25448007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Charcot-Marie-Tooth disease. ACMG/AMP Criteria applied: PS2, PP3, PM2_supporting, PS3_Strong, PS4.
GeneReviews	RCV000034136	SCV000058067	not provided	Charcot-Marie-Tooth disease type 1F		no assertion provided	literature only
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	2023-04-07	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