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UniProtKB/Swiss-Prot Q13936: Variant p.Ile1186Thr

Voltage-dependent L-type calcium channel subunit alpha-1C
Gene: CACNA1C
Chromosomal location: 12p13.3
Variant information

Variant position:  1186
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 Isoleucine (I) to Threonine (T) at position 1186 (I1186T, p.Ile1186Thr).
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 hydrophobic (I) to medium size and polar (T)
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:  Timothy syndrome (TS) [MIM:601005]: Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism. {ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:25260352, ECO:0000269|PubMed:25633834, ECO:0000269|PubMed:26253506}. 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 TS; electrophysiological phenotype, characterized by loss of current density and gain-of-function shift in activation leading to increased steady-state current; gain of function activity.
Any additional useful information about the variant.



Sequence information

Variant position:  1186
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  2221
The length of the canonical sequence.

Location on the sequence:   FIIYIIIIAFFMMNIFVGFV  I VTFQEQGEQEYKNCELDKNQ
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                         FIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNCELDKNQ

Mouse                         FIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNCELDKNQ

Rat                           FIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNCELDKNQ

Rabbit                        FIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNCELDKNQ

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 – 2221 Voltage-dependent L-type calcium channel subunit alpha-1C
Transmembrane 1162 – 1186 Helical; Name=S6 of repeat III
Repeat 887 – 1189 III
Region 1109 – 1199 Dihydropyridine binding


Literature citations

Novel Timothy syndrome mutation leading to increase in CACNA1C window current.
Boczek N.J.; Miller E.M.; Ye D.; Nesterenko V.V.; Tester D.J.; Antzelevitch C.; Czosek R.J.; Ackerman M.J.; Ware S.M.;
Heart Rhythm 12:211-219(2015)
Cited for: VARIANT TS THR-1186; CHARACTERIZATION OF VARIANT TS THR-1186;

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.
Wemhoener K.; Friedrich C.; Stallmeyer B.; Coffey A.J.; Grace A.; Zumhagen S.; Seebohm G.; Ortiz-Bonnin B.; Rinne S.; Sachse F.B.; Schulze-Bahr E.; Decher N.;
J. Mol. Cell. Cardiol. 80:186-195(2015)
Cited for: VARIANTS TS THR-28; GLY-860; THR-1186; VAL-1186; MET-1523; LYS-1544; ILE-1800 MET-1953 AND ILE-2097; CHARACTERIZATION OF VARIANTS TS THR-28; GLY-860; THR-1186; VAL-1186; MET-1523 AND LYS-1544; VARIANTS ARG-37; THR-304; LYS-477; SER-817; THR-1365; ILE-1755; GLY-1765; ASN-1787; MET-1835; ALA-1843; LYS-1948; CYS-1972; GLN-2056; ASN-2081; GLY-2122 AND SER-2174;

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.