UniProtKB/Swiss-Prot Q14397: Variant p.Pro446Leu

Glucokinase regulatory protein
Gene: GCKR
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Variant information Variant position:

446 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LB/B The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Proline (P) to Leucine (L) at position 446 (P446L, p.Pro446Leu). 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:

Similar physico-chemical property. Both residues are medium size and hydrophobic. 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
Polymorphism:

Genetic variations in GCKR define the fasting plasma glucose levels quantitative trait locus 5 (FGQTL5) [MIM:613463] (PubMed:18556336, PubMed:18678614). The normal fasting plasma glucose level is defined as less than 100 mg glucose per deciliter plasma (5.55 mmol per liter). Higher fasting plasma glucose levels predict type 2 diabetes in young adults and increases the risk of mortality (PubMed:18556336, PubMed:18678614). Additional information on the polymorphism described.
Variant description:

Protective factor against diabetes type 2; correlated with high triglyceride levels and low fasting plasma glucose levels; the mutant protein is less efficiently regulated by physiological concentrations of fructose-6 phosphate. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs1260326 [ dbSNP | Ensembl ]

Sequence information Variant position:

446 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

625 The length of the canonical sequence.
Location on the sequence:

VKEKTNHIQALAHSTVGQTL P IPLKKLFPSIISITWPLLFF 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                         VKEKTNHIQALAHSTVGQTLPIPLKKLFPSIISITWPLLFF

Mouse                         VREKSWNIQALVHSTVGQSLPAPLKKLFPSLISITWPLLFF

Rat                           VREKCQNIQALVHSTVGQSLPAPLKKLFPSLISITWPLLFF

Xenopus laevis                VKEKTSNIQVICHATAGQYLPNSLKKTIPSIIGLTWPILFL

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 – 625	Glucokinase regulatory protein
Domain	320 – 499	SIS 2
Alternative sequence	151 – 625	Missing. In isoform 2.

Literature citations
Submission
NIEHS SNPs program;
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS GLY-77; SER-256; LEU-446 AND GLN-540; Generation and annotation of the DNA sequences of human chromosomes 2 and 4.
Hillier L.W.; Graves T.A.; Fulton R.S.; Fulton L.A.; Pepin K.H.; Minx P.; Wagner-McPherson C.; Layman D.; Wylie K.; Sekhon M.; Becker M.C.; Fewell G.A.; Delehaunty K.D.; Miner T.L.; Nash W.E.; Kremitzki C.; Oddy L.; Du H.; Sun H.; Bradshaw-Cordum H.; Ali J.; Carter J.; Cordes M.; Harris A.; Isak A.; van Brunt A.; Nguyen C.; Du F.; Courtney L.; Kalicki J.; Ozersky P.; Abbott S.; Armstrong J.; Belter E.A.; Caruso L.; Cedroni M.; Cotton M.; Davidson T.; Desai A.; Elliott G.; Erb T.; Fronick C.; Gaige T.; Haakenson W.; Haglund K.; Holmes A.; Harkins R.; Kim K.; Kruchowski S.S.; Strong C.M.; Grewal N.; Goyea E.; Hou S.; Levy A.; Martinka S.; Mead K.; McLellan M.D.; Meyer R.; Randall-Maher J.; Tomlinson C.; Dauphin-Kohlberg S.; Kozlowicz-Reilly A.; Shah N.; Swearengen-Shahid S.; Snider J.; Strong J.T.; Thompson J.; Yoakum M.; Leonard S.; Pearman C.; Trani L.; Radionenko M.; Waligorski J.E.; Wang C.; Rock S.M.; Tin-Wollam A.-M.; Maupin R.; Latreille P.; Wendl M.C.; Yang S.-P.; Pohl C.; Wallis J.W.; Spieth J.; Bieri T.A.; Berkowicz N.; Nelson J.O.; Osborne J.; Ding L.; Meyer R.; Sabo A.; Shotland Y.; Sinha P.; Wohldmann P.E.; Cook L.L.; Hickenbotham M.T.; Eldred J.; Williams D.; Jones T.A.; She X.; Ciccarelli F.D.; Izaurralde E.; Taylor J.; Schmutz J.; Myers R.M.; Cox D.R.; Huang X.; McPherson J.D.; Mardis E.R.; Clifton S.W.; Warren W.C.; Chinwalla A.T.; Eddy S.R.; Marra M.A.; Ovcharenko I.; Furey T.S.; Miller W.; Eichler E.E.; Bork P.; Suyama M.; Torrents D.; Waterston R.H.; Wilson R.K.;
Nature 434:724-731(2005)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]; VARIANT LEU-446; The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.
Vaxillaire M.; Cavalcanti-Proenca C.; Dechaume A.; Tichet J.; Marre M.; Balkau B.; Froguel P.;
Diabetes 57:2253-2257(2008)
Cited for: INVOLVEMENT IN FGQTL5; VARIANT LEU-446; ASSOCIATION WITH LOWER RISK FOR DIABETES TYPE 2; The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver.
Beer N.L.; Tribble N.D.; McCulloch L.J.; Roos C.; Johnson P.R.; Orho-Melander M.; Gloyn A.L.;
Hum. Mol. Genet. 18:4081-4088(2009)
Cited for: TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANT LEU-446; Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
Orho-Melander M.; Melander O.; Guiducci C.; Perez-Martinez P.; Corella D.; Roos C.; Tewhey R.; Rieder M.J.; Hall J.; Abecasis G.; Tai E.S.; Welch C.; Arnett D.K.; Lyssenko V.; Lindholm E.; Saxena R.; de Bakker P.I.; Burtt N.; Voight B.F.; Hirschhorn J.N.; Tucker K.L.; Hedner T.; Tuomi T.; Isomaa B.; Eriksson K.F.; Taskinen M.R.; Wahlstrand B.; Hughes T.E.; Parnell L.D.; Lai C.Q.; Berglund G.; Peltonen L.; Vartiainen E.; Jousilahti P.; Havulinna A.S.; Salomaa V.; Nilsson P.; Groop L.; Altshuler D.; Ordovas J.M.; Kathiresan S.;
Diabetes 57:3112-3121(2008)
Cited for: VARIANT LEU-446; INVOLVEMENT IN FGQTL5; ASSOCIATION WITH HIGH PLASMA TRIGLYCERIDE LEVELS;

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.