ClinVar Genomic variation as it relates to human health
NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)
Variation ID: 41236 Accession: VCV000041236.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p21.2 8: 24956223 (GRCh38) [ NCBI UCSC ] 8: 24813737 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Apr 20, 2024 Mar 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006158.5:c.293A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006149.2:p.Asn98Ser missense NC_000008.11:g.24956223T>C NC_000008.10:g.24813737T>C NG_008492.1:g.5395A>G LRG_259:g.5395A>G LRG_259t1:c.293A>G LRG_259p1:p.Asn98Ser P07196:p.Asn98Ser - Protein change
- N98S
- Other names
- NEFL, ASN98SER (rs58982919)
- Canonical SPDI
- NC_000008.11:24956222:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NEFL | No evidence available | No evidence available |
GRCh38 GRCh37 |
564 | 701 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2024 | RCV000034136.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2023 | RCV000057136.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2023 | RCV000554079.7 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 7, 2023 | RCV000585792.5 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2023 | RCV000857201.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 15, 2019 | RCV001027680.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 6, 2021 | RCV001843465.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2E
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000639659.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(May 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2E
Charcot-Marie-Tooth disease type 1F Charcot-Marie-Tooth disease, dominant intermediate G
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001190244.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001337494.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1F
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368210.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic.
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Likely pathogenic
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental disorder
Sensorineural hearing loss disorder
Affected status: yes
Allele origin:
unknown
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV002102851.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Sex: female
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Pathogenic
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1F
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline,
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001429941.2
First in ClinVar: Aug 21, 2020 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Progressive peripheral neuropathy (present) , Cerebellar ataxia (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Spasticity (present) , Cerebellar ataxia (present) , Delayed gross motor development (present) , Dystonic disorder (present) , Spastic paraplegia (present) , Motor delay (present)
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Pathogenic
(Mar 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279221.9
First in ClinVar: May 29, 2016 Last updated: Apr 09, 2023 |
Comment:
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, … (more)
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) (less)
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Pathogenic
(Aug 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004101323.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1F
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002012110.2
First in ClinVar: Nov 11, 2021 Last updated: Mar 10, 2024 |
Comment:
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, … (more)
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. (less)
Clinical Features:
Global developmental delay (present) , Delayed gross motor development (present)
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Pathogenic
(May 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245758.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848847.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Apr 07, 2023)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000693719.3
First in ClinVar: Mar 14, 2018 Last updated: Apr 15, 2023 |
Comment on evidence:
In a mother and son with dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG; 617882), Berciano et al. (2016) identified a heterozygous c.293A-G transition in the NEFL … (more)
In a mother and son with dominant intermediate Charcot-Marie-Tooth disease G (CMTDIG; 617882), Berciano et al. (2016) identified a heterozygous c.293A-G transition in the NEFL gene, resulting in an asn98-to-ser (N98S) substitution at a conserved residue. The mutation was found by whole-exome sequencing after excluding mutations in several spinocerebellar ataxia and CMT genes. Functional studies of the variant were not performed. (less)
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999783.1
First in ClinVar: Dec 17, 2019 Last updated: Dec 17, 2019 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Epithelial Biology; Institute of Medical Biology, Singapore
Accession: SCV000088249.1
First in ClinVar: Oct 19, 2013 Last updated: Oct 19, 2013 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease type 1F
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000058067.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy. | Yang Y | Journal of the neurological sciences | 2016 | PMID: 27206872 |
NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype. | Berciano J | Journal of neurology | 2016 | PMID: 26645395 |
Neurofilament light polypeptide gene N98S mutation in mice leads to neurofilament network abnormalities and a Charcot-Marie-Tooth Type 2E phenotype. | Adebola AA | Human molecular genetics | 2015 | PMID: 25552649 |
Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. | Saporta MA | Experimental neurology | 2015 | PMID: 25448007 |
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301384 |
Genetic spectrum of hereditary neuropathies with onset in the first year of life. | Baets J | Brain : a journal of neurology | 2011 | PMID: 21840889 |
Neurofilament light chain polypeptide gene mutations in Charcot-Marie-Tooth disease: nonsense mutation probably causes a recessive phenotype. | Abe A | Journal of human genetics | 2009 | PMID: 19158810 |
Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. | Jordanova A | Brain : a journal of neurology | 2003 | PMID: 12566280 |
Identification of novel sequence variants in the neurofilament-light gene in a Japanese population: analysis of Charcot-Marie-Tooth disease patients and normal individuals. | Yoshihara T | Journal of the peripheral nervous system : JPNS | 2002 | PMID: 12477167 |
Text-mined citations for rs58982919 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.