8-24956493-G-C

Position:

• chr8-24956493-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_006158.5(NEFL):​c.23C>G​(p.Pro8Arg) variant causes a missense change involving the alteration of a non-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. P8L) has been classified as 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:3 U:1 O:2
• Conservation: PhyloP100: 2.76

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Head (size 90) in uniprot entity NFL_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) 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 chr8-24956493-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEFL	NM_006158.5	c.23C>G	p.Pro8Arg	missense_variant	1/4	ENST00000610854.2	NP_006149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEFL	ENST00000610854.2	c.23C>G	p.Pro8Arg	missense_variant	1/4	1	NM_006158.5	ENSP00000482169.2
ENSG00000272157	ENST00000607735.2	n.553G>C		non_coding_transcript_exon_variant	1/1	6
NEFL	ENST00000615973.1	n.229C>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 8 of the NEFL protein (p.Pro8Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 12566280, 17620486, 22206013, 28501821). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NEFL protein function. Experimental studies have shown that this missense change affects NEFL function (PMID: 22155564, 23618875). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2020

The p.P8R variant (also known as c.23C>G), located in coding exon 1 of the NEFL gene, results from a C to G substitution at nucleotide position 23. The proline at codon 8 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This alteration has been reported in the heterozygous form in multiple affected individuals with Charcot-Marie-Tooth (CMT) disease, and was reported to occur de novo in one affected individual (Jordanova A et al. Brain, 2003 Mar;126:590-7; Miltenberger-Miltenyi G et al. Arch Neurol, 2007 Jul;64:966-70; Lin KP et al. PLoS One, 2011 Dec;6:e29393; Horga A et al. J Neurol Neurosurg Psychiatry, 2017 07;88:575-585). Functional studies have shown that this alteration has an effect on intermediate filament formation, resulting in mitochondrial and axonal abnormalities (Zhai J et al. Hum Mol Genet, 2007 Dec;16:3103-16; Tradewell ML et al. J Neuropathol Exp Neurol, 2009 Jun;68:642-52). The NEFL c.22_23delCCinsAG alteration, which results in an identical amino acid change, has been reported to segregate with disease in a family displaying autosomal dominant inheritance of CMT (De Jonghe P et al. Ann Neurol, 2001 Feb;49:245-9). Based on the supporting evidence, this variant is likely to be causative of autosomal dominant CMT, type 1F/2E; however, its clinical significance for autosomal recessive CMT, type 1F/2E is unclear. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Benign	0.95
DEOGEN2	Uncertain	0.48	T;.;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Uncertain	0.45	T;T;T
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.49	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.60
MVP		0.85
GERP RS		5.6
Varity_R		0.57
gMVP		0.85

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: rs61491953; hg19: chr8-24814007; COSMIC: COSV55337963; COSMIC: COSV55337963;