UniProtKB/SwissProt variant VAR

Variant information

Variant position:

484

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 Phenylalanine (F) to Leucine (L) at position 484 (F484L, p.Phe484Leu).

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 aromatic (F) to medium size and hydrophobic (L)

The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:

0

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:

Myotonia congenita, autosomal dominant (MCAD) [MIM:160800]: A non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. The autosomal dominant form (Thomsen disease) is less common and less severe than the autosomal recessive one (Becker disease). A milder form of autosomal dominant myotonia is characterized by isolated myotonia without muscle weakness, hypotrophy, or hypertrophy (myotonia levior). {ECO:0000269|PubMed:12661046, ECO:0000269|PubMed:26096614, ECO:0000269|PubMed:27653901, ECO:0000269|PubMed:27666773, ECO:0000269|PubMed:7581380, ECO:0000269|PubMed:7981750, ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:8533761, ECO:0000269|PubMed:8845168, ECO:0000269|PubMed:9122265, ECO:0000269|PubMed:9566422, ECO:0000269|PubMed:9736777}. 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 MCAD; reduced chloride transport; changed calcium channel activity; changed channel gating; no dominant negative effect.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs1312002847 [ dbSNP | Ensembl ]

Sequence information

Variant position:

484

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

Protein sequence length:

988

The length of the canonical sequence.

Location on the sequence:

FVMKFWMSIVATTMPIPCGG F MPVFVLGAAFGRLVGEIMAM

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                         FVMKFWMSIVATTMPIPCGGFMPVFVLGAAFGRLVGEIMAM

                              FIMKFWMSIVATTMPIPCGGFMPVFVLGAAFGRLVGEIMAM

Mouse                         FVMKFWMSIVATTMPIPCGGFMPVFVLGAAFGRLVGEIMAM

Rat                           FVMKFWMSIVATTMPIPCGGFMPVFVLGAAFGRLVGEIMAM

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.

Type	Positions	Description
Chain	1 – 988	Chloride channel protein 1
Transmembrane	479 – 498	Helical
Motif	482 – 486	Selectivity filter part_3
Binding site	484 – 484	Chloride; via amide nitrogen
Mutagenesis	496 – 496	R -> K. Changed gating of the channel.
Mutagenesis	499 – 499	G -> KE. Changed gating of the channel.
Mutagenesis	499 – 499	G -> Q. No effect on gating of the channel.
Mutagenesis	500 – 500	E -> Q. No effect on channel function.
Helix	484 – 502

Literature citations

ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation.
Imbrici P.; Maggi L.; Mangiatordi G.F.; Dinardo M.M.; Altamura C.; Brugnoni R.; Alberga D.; Pinter G.L.; Ricci G.; Siciliano G.; Micheli R.; Annicchiarico G.; Lattanzi G.; Nicolotti O.; Morandi L.; Bernasconi P.; Desaphy J.F.; Mantegazza R.; Camerino D.C.;
J. Physiol. (Lond.) 593:4181-4199(2015)
Cited for: VARIANTS MCAD PRO-198 AND LEU-484; CHARACTERIZATION OF VARIANTS MCAD PRO-198 AND LEU-484; VARIANTS MCAR PRO-628 AND GLY-640; CHARACTERIZATION OF VARIANTS MCAR PRO-628 AND GLY-640;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P35523: Variant p.Phe484Leu