rs58982919

chr8-24956223-T-C

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. N98D) 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr8-24956224-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2579045.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
NEFL	NM_006158.5	c.293A>G	p.Asn98Ser	missense_variant	1/4	ENST00000610854.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEFL	ENST00000610854.2	c.293A>G	p.Asn98Ser	missense_variant	1/4	1	NM_006158.5	P1
	ENST00000607735.2	n.283T>C		non_coding_transcript_exon_variant	1/1
NEFL	ENST00000615973.1	n.499A>G		non_coding_transcript_exon_variant	1/1

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

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	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. -
Uncertain significance, no assertion criteria provided	research	Genesis Genome Database	Aug 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 07, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 28, 2021	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2023	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) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

May 15, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 07, 2023

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 06, 2021

- -

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;