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UniProtKB/Swiss-Prot P07196: Variant p.Glu396Lys

Neurofilament light polypeptide
Gene: NEFL
Variant information

Variant position:  396
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Glutamate (E) to Lysine (K) at position 396 (E396K, p.Glu396Lys).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and acidic (E) to large size and basic (K)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Charcot-Marie-Tooth disease 2E (CMT2E) [MIM:607684]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:10841809, ECO:0000269|PubMed:11220745, ECO:0000269|PubMed:12481988, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:17052987, ECO:0000269|PubMed:22206013, ECO:0000269|PubMed:25802885}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in disease:  Charcot-Marie-Tooth disease, dominant intermediate G (CMTDIG) [MIM:617882]: An autosomal dominant, intermediate form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Dominant intermediate forms are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. CMTDIG is phenotypically variable. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. {ECO:0000269|PubMed:14733962, ECO:0000269|PubMed:17052987, ECO:0000269|PubMed:25877835, ECO:0000269|PubMed:26645395}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In CMTDIG and CMT2E.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  396
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  543
The length of the canonical sequence.

Location on the sequence:   LNVKMALDIEIAAYRKLLEG  E ETRLSFTSVGSITSGYSQSS
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         LNVKMALDIEIAAYRKLLEGEETRLSFTSVGSITSGYSQSS

Mouse                         LNVKMALDIEIAAYRKLLEGEETRLSFTSVGSITSGYSQSS

Rat                           LNVKMALDIEIAAYRKLLEGEETRLSFTSVGSITSGYSQSS

Pig                           LNVKMALDIEIAAYRKLLEGEETRLSFTSVGSLTTGYSQSS

Bovine                        LNVKMALDIEIAAYRKLLEGEETRLSFTSVGSLTTGYTQSS

Xenopus laevis                LNVKMALDIEIAAYRKLLEGEETRLSFSGVGAITSGYTQSA

Xenopus tropicalis            LNVKMALDIEIAAYRKLLEGEETRLSFSGVGAITSGYTQSA

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 2 – 543 Neurofilament light polypeptide
Domain 90 – 400 IF rod
Region 281 – 396 Coil 2B


Literature citations

Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients.
Choi B.-O.; Lee M.S.; Shin S.H.; Hwang J.H.; Choi K.-G.; Kim W.-K.; Sunwoo I.N.; Kim N.K.; Chung K.W.;
Hum. Mutat. 24:185-186(2004)
Cited for: VARIANT CMT2E PRO-336; VARIANT CMT1F LYS-396;

The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy.
Zuechner S.; Vorgerd M.; Sindern E.; Schroeder J.M.;
Neuromuscul. Disord. 14:147-157(2004)
Cited for: VARIANT CMTDIG LYS-396;

Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.
Fabrizi G.M.; Cavallaro T.; Angiari C.; Cabrini I.; Taioli F.; Malerba G.; Bertolasi L.; Rizzuto N.;
Brain 130:394-403(2007)
Cited for: VARIANTS MET-213 AND ASN-468; VARIANTS CMT2E SER-22; PRO-268 AND 322-CYS--ASN-326 DEL; VARIANT CMTDIG LYS-396;

The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in Taiwan.
Lin K.P.; Soong B.W.; Yang C.C.; Huang L.W.; Chang M.H.; Lee I.H.; Antonellis A.; Lee Y.C.;
PLoS ONE 6:E29393-E29393(2011)
Cited for: VARIANTS CMT2E ARG-8; SER-22 AND LYS-396;

NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype.
Berciano J.; Garcia A.; Peeters K.; Gallardo E.; De Vriendt E.; Pelayo-Negro A.L.; Infante J.; Jordanova A.;
J. Neurol. 262:1289-1300(2015)
Cited for: VARIANT CMTDIG LYS-396; INVOLVEMENT IN CMTDIG;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.