UniProtKB/SwissProt variant VAR

Variant information

Variant position:

858

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 Histidine (H) at position 858 (R858H, p.Arg858His).

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 (H)

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:

Long QT syndrome 8 (LQT8) [MIM:618447]: A form of long QT syndrome, a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. LQT8 transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance. {ECO:0000269|PubMed:23677916, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:25633834, ECO:0000269|PubMed:30345660}. 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 LQT8; gain-of-function effect on channel activity; slower inactivation.

Any additional useful information about the variant.

Sequence information

Variant position:

858

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:

PNPETTGEEDEEEPEMPVGP R PRPLSELHLKEKAVPMPEAS

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                         PNPETTGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEAS

Mouse                         SNPDTAGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEAS

Rat                           SNPDTAGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEAS

Rabbit                        PNPETTGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEAS

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 – 2221	Voltage-dependent L-type calcium channel subunit alpha-1C
Topological domain	746 – 900	Cytoplasmic
Region	829 – 876	Interaction with STAC2

Literature citations

Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes.
Fukuyama M.; Wang Q.; Kato K.; Ohno S.; Ding W.G.; Toyoda F.; Itoh H.; Kimura H.; Makiyama T.; Ito M.; Matsuura H.; Horie M.;
Europace 16:1828-1837(2014)
Cited for: VARIANTS LQT8 SER-381; ILE-456; ASP-582; HIS-858 AND CYS-1831; CHARACTERIZATION OF VARIANTS LQT8 SER-381; ILE-456; ASP-582; HIS-858 AND CYS-1831; FUNCTION; SUBUNIT; SUBCELLULAR LOCATION; INTERACTION WITH CACNB2 AND CACNA2D1;

Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy.
Gardner R.J.M.; Crozier I.G.; Binfield A.L.; Love D.R.; Lehnert K.; Gibson K.; Lintott C.J.; Snell R.G.; Jacobsen J.C.; Jones P.P.; Waddell-Smith K.E.; Kennedy M.A.; Skinner J.R.;
Mol. Genet. Genomic Med. 7:E00476-E00476(2019)
Cited for: VARIANT LQT8 HIS-858;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot Q13936: Variant p.Arg858His