rs28928910
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
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
Consequence
NM_006158.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
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 | P1 | |
ENST00000607735.2 | n.512G>A | non_coding_transcript_exon_variant | 1/1 | |||||||
NEFL | ENST00000615973.1 | n.270C>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 37
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2E Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2006 | - - |
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). - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
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) - |
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. - |
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;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 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at