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UniProtKB/Swiss-Prot P51787: Variant p.Gly589Asp

Potassium voltage-gated channel subfamily KQT member 1
Gene: KCNQ1
Variant information

Variant position:  589
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 Glycine (G) to Aspartate (D) at position 589 (G589D, p.Gly589Asp).
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 glycine (G) to medium size and acidic (D)
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:  Jervell and Lange-Nielsen syndrome 1 (JLNS1) [MIM:220400]: An autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. {ECO:0000269|PubMed:10090886, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:18441444, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:9781056}. 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:  Long QT syndrome 1 (LQT1) [MIM:192500]: 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. {ECO:0000269|PubMed:10024302, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10220146, ECO:0000269|PubMed:10367071, ECO:0000269|PubMed:10409658, ECO:0000269|PubMed:10482963, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11799244, ECO:0000269|PubMed:12442276, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18165683, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:19540844, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:19808498, ECO:0000269|PubMed:21241800, ECO:0000269|PubMed:24184248, ECO:0000269|PubMed:24269949, ECO:0000269|PubMed:24713462, ECO:0000269|PubMed:25037568, ECO:0000269|PubMed:25139741, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:8528244, ECO:0000269|PubMed:8818942, ECO:0000269|PubMed:8872472, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9272155, ECO:0000269|PubMed:9302275, ECO:0000269|PubMed:9312006, ECO:0000269|PubMed:9323054, ECO:0000269|PubMed:9386136, ECO:0000269|PubMed:9482580, ECO:0000269|PubMed:9570196, ECO:0000269|PubMed:9641694, ECO:0000269|PubMed:9693036, ECO:0000269|PubMed:9702906, ECO:0000269|PubMed:9799083, ECO:0000269|PubMed:9927399, ECO:0000269|Ref.31}. 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 LQT1 and JLNS1; affects plasma membrane localization; strongly reduces potassium current; impairs binding to AKAP9 and the targeting protein kinase A (PKA) catalytic subunit and protein phosphatase 1 (PP1).
Any additional useful information about the variant.

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



Sequence information

Variant position:  589
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  676
The length of the canonical sequence.

Location on the sequence:   KPSLFISVSEKSKDRGSNTI  G ARLNRVEDKVTQLDQRLALI
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                         KPSLFISVSEKSKDRGSNTIGARLNRVEDKVTQLDQRLALI

Mouse                         KPSLFIPISEKSKDRGSNTIGARLNRVEDKVTQLDQRLVII

Rat                           KPSLFIPISEKSKDRGSNTIGARLNRVEDKVTQLDQRLVII

Rabbit                        KPSLFVPISEKSKDRGSNSIGARLNRVEDKVTQLDQRLVLI

Xenopus laevis                KPSLFLSVSDKVKDKGINTIGSRLNRVEDKVTQMDHKLNLI

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 – 676 Potassium voltage-gated channel subfamily KQT member 1
Topological domain 349 – 676 Cytoplasmic
Region 588 – 616 Interaction with AKAP9
Region 589 – 620 C-terminal assembly domain
Coiled coil 585 – 621
Mutagenesis 589 – 589 G -> M. No effect.
Mutagenesis 590 – 590 A -> W. Reduced cell surface expression and strongly reduced potassium current.
Mutagenesis 593 – 593 N -> G. Reduced cell surface expression and moderately reduced potassium current.
Mutagenesis 602 – 602 L -> A. Does not interact with AKAP9 and the targeting protein kinase A (PKA) catalytic subunit and protein phosphatase 1 (PP1); when associated with I-609.
Mutagenesis 609 – 609 I -> A. Does not interact with AKAP9 and the kinase A (PKA) catalytic subunit and protein phosphatase 1 (PP1); when associated with L-602.
Helix 588 – 609


Literature citations

Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.
Marx S.O.; Kurokawa J.; Reiken S.; Motoike H.; D'Armiento J.; Marks A.R.; Kass R.S.;
Science 295:496-499(2002)
Cited for: INTERACTION WITH AKAP9; PHOSPHORYLATION AT SER-27; CHARACTERIZATION OF VARIANT LQT1 ASP-589; MUTAGENESIS OF SER-27; LEU-602 AND ILE-609;

The KCNQ1 (Kv7.1) COOH terminus, a multitiered scaffold for subunit assembly and protein interaction.
Wiener R.; Haitin Y.; Shamgar L.; Fernandez-Alonso M.C.; Martos A.; Chomsky-Hecht O.; Rivas G.; Attali B.; Hirsch J.A.;
J. Biol. Chem. 283:5815-5830(2008)
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 574-622; INTERACTION WITH CALM; SUBCELLULAR LOCATION; MUTAGENESIS OF GLY-589; ALA-590 AND ASN-593; CHARACTERIZATION OF VARIANT LQT1 ASP-589; TETRAMERIZATION;

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.
Kapplinger J.D.; Tester D.J.; Salisbury B.A.; Carr J.L.; Harris-Kerr C.; Pollevick G.D.; Wilde A.A.; Ackerman M.J.;
Heart Rhythm 6:1297-1303(2009)
Cited for: VARIANTS LQT1 VAL-2; SER-7; THR-46; 64-PRO--PRO-70 DEL; PHE-66; THR-73; CYS-111; LEU-117; LEU-127; ILE-133; PRO-134; ALA-144; MET-153; MET-162; ARG-168; MET-172; CYS-174; HIS-174; THR-178; SER-179; HIS-184; ARG-186; GLN-190; LEU-190; TRP-195; VAL-198; ALA-199; MET-204; MET-215; MET-224; LEU-225; CYS-231; HIS-231; ASN-235; GLY-241; ASN-242; CYS-243; PRO-250; MET-254; CYS-259; LEU-259; VAL-262; PRO-266; SER-268; ASP-269; SER-269; ASP-272; PHE-273; VAL-274; LEU-277; PRO-277; GLU-280; CYS-281; PRO-282; GLY-283; ASP-292; CYS-293; GLU-302; VAL-302; PRO-303; ARG-305; SER-305; ARG-306; ILE-312; CYS-314; SER-314; CYS-315; VAL-316; SER-320; ALA-322; MET-322; ARG-325; TYR-339; GLU-341; GLY-341; VAL-341; PHE-342; LEU-343; ARG-350; SER-351; ARG-354; MET-360; ARG-362; HIS-365; GLN-366; TRP-366; HIS-374; GLY-379; LYS-385; PRO-389; THR-391 INS; TRP-397; ARG-398; GLU-446; LEU-448; TRP-451; SER-460; LEU-477; TRP-511; GLN-518; ARG-520; SER-522; GLY-524; THR-525; VAL-525; TRP-533; GLN-539; TRP-539; ILE-541; LYS-543; LEU-546; ARG-547; CYS-555; HIS-555; SER-555; GLU-557; PHE-566; PRO-566; TYR-566; THR-567; ARG-568; GLU-569; LEU-571; MET-587; ASP-589; CYS-591; HIS-591; GLN-594; PRO-594; GLU-596 DEL; LYS-596; MET-600; ASN-611; HIS-614 DEL; SER-626 AND ARG-635;

Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP(2).
Dvir M.; Strulovich R.; Sachyani D.; Ben-Tal Cohen I.; Haitin Y.; Dessauer C.; Pongs O.; Kass R.; Hirsch J.A.; Attali B.;
J. Cell Sci. 127:3943-3955(2014)
Cited for: CHARACTERIZATION OF VARIANTS LQT1 LEU-546; CYS-555; HIS-555; GLU-557 AND ASP-589; INTERACTION WITH KCNE1 AND AKAP9; SUBCELLULAR LOCATION; FUNCTION;

Cellular mechanisms of mutations in Kv7.1: auditory functions in Jervell and Lange-Nielsen syndrome vs. Romano-Ward syndrome.
Mousavi Nik A.; Gharaie S.; Jeong Kim H.;
Front. Cell. Neurosci. 9:32-32(2015)
Cited for: CHARACTERIZATION OF VARIANTS LQT1 ASN-242; PRO-243; HIS-250; VAL-306; ASN-317; ASP-586 AND MET-619; CHARACTERIZATION OF VARIANTS JLNS1 PHE-248; ILE-311; MET-322 AND ASP-589;

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.