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UniProtKB/Swiss-Prot P35499: Variant p.Arg1448Cys

Sodium channel protein type 4 subunit alpha
Gene: SCN4A
Variant information

Variant position:  1448
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 Arginine (R) to Cysteine (C) at position 1448 (R1448C, p.Arg1448Cys).
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 large size and basic (R) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
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:  Paramyotonia congenita of von Eulenburg (PMC) [MIM:168300]: An autosomal dominant channelopathy characterized by myotonia, increased by exposure to cold, intermittent flaccid paresis, not necessarily dependent on cold or myotonia, lability of serum potassium, non-progressive nature and lack of atrophy or hypertrophy of muscles. In some patients, myotonia is not increased by cold exposure (paramyotonia without cold paralysis). Patients may have a combination phenotype of PMC and HYPP. {ECO:0000269|PubMed:10369308, ECO:0000269|PubMed:10727489, ECO:0000269|PubMed:1310898, ECO:0000269|PubMed:1316765, ECO:0000269|PubMed:1338909, ECO:0000269|PubMed:15318338, ECO:0000269|PubMed:15790667, ECO:0000269|PubMed:16786525, ECO:0000269|PubMed:18166706, ECO:0000269|PubMed:18690054, ECO:0000269|PubMed:19077043, ECO:0000269|PubMed:20076800, ECO:0000269|PubMed:8242056, ECO:0000269|PubMed:8308722, ECO:0000269|PubMed:8388676, ECO:0000269|PubMed:8580427}. 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 PMC; changes the voltage-gated sodium channel activity; increases membrane hyperexcitability at low temperature; decreases channel activation, deactivation, fast inactivation and recovery delay from fast inactivation.
Any additional useful information about the variant.

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



Sequence information

Variant position:  1448
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1836
The length of the canonical sequence.

Location on the sequence:   IVGLALSDLIQKYFVSPTLF  R VIRLARIGRVLRLIRGAKGI
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                         IVGLALSDLIQKYFVSPTLFRVIRLARIGRVLRLIRGAKGI

Mouse                         IVGLALSDLIQKYFVSPTLFRVIRLARIGRVLRLIRGAKGI

Rat                           IVGLALSDLIQKYFVSPTLFRVIRLARIGRVLRLIRGAKGI

Horse                         IVGLALSDLIQKYFVSPTLFRVIRLARIGRVLRLIRGAKGI

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 1 – 1836 Sodium channel protein type 4 subunit alpha
Transmembrane 1446 – 1462 Helical; Name=S4 of repeat IV
Repeat 1335 – 1633 IV
Helix 1447 – 1450


Literature citations

Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita.
Ptacek L.J.; George A.L. Jr.; Barchi R.L.; Griggs R.C.; Riggs J.E.; Robertson M.; Leppert M.F.;
Neuron 8:891-897(1992)
Cited for: VARIANTS PMC CYS-1448 AND HIS-1448;

Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M.
Dice M.S.; Abbruzzese J.L.; Wheeler J.T.; Groome J.R.; Fujimoto E.; Ruben P.C.;
Muscle Nerve 30:277-288(2004)
Cited for: VARIANTS PMC MET-1313 AND CYS-1448; CHARACTERIZATION OF VARIANTS PMC MET-1313 AND CYS-1448; FUNCTION; SUBCELLULAR LOCATION;

What causes paramyotonia in the United Kingdom? Common and new SCN4A mutations revealed.
Matthews E.; Tan S.V.; Fialho D.; Sweeney M.G.; Sud R.; Haworth A.; Stanley E.; Cea G.; Davis M.B.; Hanna M.G.;
Neurology 70:50-53(2008)
Cited for: VARIANTS PMC LYS-270; MET-704; ALA-1306; GLU-1306; MET-1313; PRO-1436; CYS-1448; HIS-1448; LEU-1448; GLU-1456; SER-1473 AND MET-1589;

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.