8-24956223-T-C

Variant names:

• chr8-24956223-T-C
• rs58982919
• NM_006158.5:c.293A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_006158.5(NEFL):​c.293A>G​(p.Asn98Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N98T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:2
• Conservation: PhyloP100: 7.93

Genes affected

NEFL (HGNC:7739): (neurofilament light chain) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene encodes the light chain neurofilament protein. Mutations in this gene cause Charcot-Marie-Tooth disease types 1F (CMT1F) and 2E (CMT2E), disorders of the peripheral nervous system that are characterized by distinct neuropathies. A pseudogene has been identified on chromosome Y. [provided by RefSeq, Oct 2008]

ENSG00000272157 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 31) in uniprot entity NFL_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_006158.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-24956223-T-G is described in Lovd as [Likely_pathogenic].
• PP5: Variant 8-24956223-T-C is Pathogenic according to our data. Variant chr8-24956223-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 41236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-24956223-T-C is described in Lovd as [Pathogenic]. Variant chr8-24956223-T-C is described in Lovd as [Likely_pathogenic]. Variant chr8-24956223-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEFL	NM_006158.5	c.293A>G	p.Asn98Ser	missense_variant	Exon 1 of 4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.293A>G	p.Asn98Ser	missense_variant	Exon 1 of 4	1	NM_006158.5	ENSP00000482169.2
ENSG00000272157	ENST00000607735.2	n.283T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
NEFL	ENST00000615973.1	n.499A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:3 Uncertain:1

Aug 14, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Charcot-Marie-Tooth disease type 1F Pathogenic:3 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 28, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. -

Mar 14, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25552649). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: NA (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.65 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000041236 /PMID: 12477167 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 12566280). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12566280, 25552649, 26645395, 32376792). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Asn98Asp, p.Asn98His, p.Asn98Lys, p.Asn98Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372433, VCV002579045, VCV002664371 /PMID: 31211173 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 20, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEFL: PS2:Very Strong, PM2, PS3:Moderate, PS4:Moderate, PP1 -

Charcot-Marie-Tooth disease type 1F;C1843225:Charcot-Marie-Tooth disease type 2E;C4693509:Charcot-Marie-Tooth disease, dominant intermediate G Pathogenic:1

May 15, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2E Pathogenic:1

Oct 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Charcot-Marie-Tooth disease, dominant intermediate G Pathogenic:1

Apr 07, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Developmental disorder;C0018784:Sensorineural hearing loss disorder Pathogenic:1

Oct 06, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	35
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.95	D;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Uncertain	0.67	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.99
MVP		0.80
GERP RS		5.3
Varity_R		0.86
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58982919; hg19: chr8-24813737;