rs28928910

Positions:

• chr8-24956452-G-A
• chr8-24956452-G-C
• chr8-24956452-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The NM_006158.5(NEFL):​c.64C>T​(p.Pro22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. P22R) 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:7 O:2
• Conservation: PhyloP100: 1.91

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 13 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 chr8-24956451-G-C is described in Lovd as [Pathogenic].
• PP5: Variant 8-24956452-G-A is Pathogenic according to our data. Variant chr8-24956452-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-24956452-G-A is described in Lovd as [Pathogenic]. Variant chr8-24956452-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28821254). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEFL	NM_006158.5	c.64C>T	p.Pro22Ser	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.64C>T	p.Pro22Ser	missense_variant	1/4	1	NM_006158.5	ENSP00000482169.2
ENSG00000272157	ENST00000607735.2	n.512G>A		non_coding_transcript_exon_variant	1/1	6
NEFL	ENST00000615973.1	n.270C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Alfa AF: 0.000313 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This missense change has been observed in individuals with mixed axonal and demyelinating neuropathy (PMID: 12481988, 15111691, 19286384). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NEFL function (PMID: 16452125, 21168446). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 14029). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 22 of the NEFL protein (p.Pro22Ser). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2006	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2022	This variant segregates with autosomal dominant CMT in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 16452125, 23230147, 20421365, 21168446) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

The p.P22S pathogenic mutation (also known as c.64C>T), located in coding exon 1 of the NEFL gene, results from a C to T substitution at nucleotide position 64. The proline at codon 22 is replaced by serine, an amino acid with similar properties. This variant was found to segregate with autosomal dominant Charcot-Marie-Tooth disease in one multigenerational family (Georgiou DM et al. Neurogenetics, 2002 Oct;4:93-6). This alteration has also been detected in the heterozygous state in individuals with mixed demyelinating and axonal neuropathy (Fabrizi GM et al. Neurology, 2004 Apr;62:1429-31; Bhagavati S et al. J Clin Neurosci, 2009 Jun;16:830-1). Functional studies have shown that this alteration led to abnormal neurofilament assembly and recapitulates the neuropathy phenotype in a mouse model (Fabrizi GM et al. Neurology, 2004 Apr;62:1429-31; Dequen F et al. Hum Mol Genet, 2010 Jul;19:2616-29; Miao L et al. J Cell Sci, 2013 Jan;126:427-36; Stone EJ et al. Cytoskeleton (Hoboken), 2019 07;76:423-439). Based on the supporting evidence, this variant is expected to be causative of Charcot-Marie-Tooth (CMT) disease, type 1F/2E; however, its clinical significance for the autosomal recessive form of NEFL-related CMT is unclear. -

Peripheral neuropathy;C0728829:Pes cavus;C1836450:Distal lower limb muscle weakness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 03, 2014

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Peripheral neuropathy;C0239830:Hand muscle atrophy;C0427065:Distal muscle weakness;C0878575:Peripheral demyelination;C1857640:Decreased nerve conduction velocity Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 11, 2014

- -

Charcot-Marie-Tooth disease type 1C Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.;T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.29	T;T;T
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.57	T;.;T
Polyphen		0.24	B;.;.
Vest4		0.19
MVP		0.86
GERP RS		5.3
Varity_R		0.29
gMVP		0.81

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: rs28928910; hg19: chr8-24813966;