rs61491953

Positions:

• chr8-24956493-G-A
• chr8-24956493-G-C
• chr8-24956493-G-T

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.23C>T​(p.Pro8Leu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEFL NM_006158.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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-T is described in Lovd as [Pathogenic].
• PP5: Variant 8-24956493-G-A is Pathogenic according to our data. Variant chr8-24956493-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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>T	p.Pro8Leu	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>T	p.Pro8Leu	missense_variant	1/4	1	NM_006158.5	ENSP00000482169	P1
	ENST00000607735.2	n.553G>A		non_coding_transcript_exon_variant	1/1
NEFL	ENST00000615973.1	n.229C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447836 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 718908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.23C>T (p.P8L) alteration is located in exon 1 (coding exon 1) of the NEFL gene. This alteration results from a C to T substitution at nucleotide position 23, causing the proline (P) at amino acid position 8 to be replaced by a leucine (L). This variant is expected to be causative of autosomal dominant NEFL-related Charcot-Marie-Tooth; however, its clinical significance for autosomal recessive NEFL-related Charcot-Marie-Tooth disease is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the heterozygous state in multiple individuals with clinical features of autosomal dominant NEFL-related Charcot-Marie-Tooth disease (Kim, 2022; Jordanova, 2003; Abe, 2020). This amino acid position is not well conserved in available vertebrate species. Based on internal structural analysis, P8L is deleterious. The variant has an important role in aggregate formation and 14-3-3 protein association. In addition, there is another pathogenic variant (P8R) at the same position (Zhou, 2022; Miao, 2020; Perez-Olle, 2004). Functional studies show aberrant neurofilament formation in vitro compared to controls (Miao, 2020; Perez-Olle, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro8 amino acid residue in NEFL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12393795, 12566280, 17620486). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 66689). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 12566280, 19158810). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 8 of the NEFL protein (p.Pro8Leu). -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D;.;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Uncertain	0.47	T;T;T
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.73	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.34
MVP		0.78
GERP RS		5.6
Varity_R		0.60
gMVP		0.80

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;