UniProtKB/Swiss-Prot P35557: Variant p.Gly261Arg

Hexokinase-4
Gene: GCK
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Variant information Variant position:

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

LP/P [Disclaimer] 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 Glycine (G) to Arginine (R) at position 261 (G261R, p.Gly261Arg). 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 large size and basic (R) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-2 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
Variant description:

In MODY2 and PNDM1; pathogenic; highly decreased glucokinase activity; decreased affinity for glucose. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs104894008 [ dbSNP | Ensembl ]

Sequence information Variant position:

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

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

VELVEGDEGRMCVNTEWGAF G DSGELDEFLLEYDRLVDESS 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                         VELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRLVDESS

Mouse                         VELVEGDEGRMCVNTEWGAFGNSGELDEFLLEYDRMVDESS

Rat                           VELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRMVDESS

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 – 465	Hexokinase-4
Domain	10 – 454	Hexokinase
Region	204 – 443	Hexokinase large subdomain
Binding site	256 – 256
Mutagenesis	256 – 256	E -> A. Inactive enzyme with no glucokinase activity.
Turn	260 – 263

Literature citations
Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.
Stoffel M.; Froguel P.; Takeda J.; Zouali H.; Vionnet N.; Nishi S.; Weber I.T.; Harrison R.W.; Pilkis S.J.; Lesage S.; Vaxillaire M.; Velho G.; Sun F.; Iris F.; Passa P.; Cohen D.; Bell G.I.;
Proc. Natl. Acad. Sci. U.S.A. 89:7698-7702(1992)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS MODY2 MET-228 AND ARG-261; Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus.
Sakura H.; Eto K.; Kadowaki H.; Simokawa K.; Ueno H.; Koda N.; Fukushima Y.; Akanuma Y.; Yazaki Y.; Kadowaki T.;
J. Clin. Endocrinol. Metab. 75:1571-1573(1992)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANT THR-107; VARIANT MODY2 ARG-261; Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.
Velho G.; Blanche H.; Vaxillaire M.; Bellanne-Chantelot C.; Pardini V.C.; Timsit J.; Passa P.; Deschamps I.; Robert J.-J.; Weber I.T.; Marotta D.; Pilkis S.J.; Lipkind G.M.; Bell G.I.; Froguel P.;
Diabetologia 40:217-224(1997)
Cited for: VARIANTS MODY2 SER-53; ALA-80; ARG-137; PRO-168; 186-ARG--GLN-465 DEL; THR-210; ARG-213; MET-226; 248-GLU--GLN-465 DEL; ARG-261; LEU-336; 360-SER--GLN-465 DEL AND MET-367; Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain.
Estalella I.; Rica I.; Perez de Nanclares G.; Bilbao J.R.; Vazquez J.A.; San Pedro J.I.; Busturia M.A.; Castano L.;
Clin. Endocrinol. (Oxf.) 67:538-546(2007)
Cited for: VARIANTS MODY2 GLU-16; ASN-19; PRO-20; TRP-36; SER-43; SER-44; 61-TYR--GLN-465 DEL; SER-61; LYS-70; ARG-72; PRO-77; GLU-78; ASP-80; ILE-82; HIS-108; PRO-116; LEU-182; 186-ARG--GLN-465 DEL; TYR-187; TRP-191; LEU-200; THR-202; MET-206; MET-209; SER-223; ARG-224; SER-227; MET-228; ARG-233; 234-TYR--GLN-465 DEL; GLY-252; ALA-255; LYS-256; ARG-261; LYS-265; LYS-298; TRP-308; HIS-377; VAL-379; LEU-383; 399-GLU--GLN-465 DEL; PHE-411; PRO-416; GLU-420 AND TRP-441; Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis.
Beer N.L.; Osbak K.K.; van de Bunt M.; Tribble N.D.; Steele A.M.; Wensley K.J.; Edghill E.L.; Colcough K.; Barrett A.; Valentinova L.; Rundle J.K.; Raimondo A.; Grimsby J.; Ellard S.; Gloyn A.L.;
Diabetes Care 35:1482-1484(2012)
Cited for: VARIANTS MODY2 HIS-43; ASP-68; ASN-217; MET-225; LYS-248; ARG-261 AND ARG-261; CHARACTERIZATION OF VARIANTS MODY2 HIS-43; ASP-68; ASN-217; MET-225; LYS-248; ARG-261 AND ARG-261; Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
Raimondo A.; Chakera A.J.; Thomsen S.K.; Colclough K.; Barrett A.; De Franco E.; Chatelas A.; Demirbilek H.; Akcay T.; Alawneh H.; Flanagan S.E.; Van De Bunt M.; Hattersley A.T.; Gloyn A.L.; Ellard S.;
Hum. Mol. Genet. 23:6432-6440(2014)
Cited for: VARIANTS PNDM1 LYS-40; CYS-43; ASP-50; ARG-72; THR-151; PRO-164; ALA-168; ARG-169; ARG-261; THR-393; LEU-397; LEU-441 AND THR-449; CHARACTERIZATION OF VARIANTS PNDM1 LYS-40; CYS-43; ASP-50; ARG-72; ALA-168; ARG-261; THR-393; LEU-397; LEU-441 AND THR-449; VARIANTS MODY2 ASN-160 AND MET-226; CHARACTERIZATION OF VARIANT MODY2 ASN-160 AND MET-226; FUNCTION; CATALYTIC ACTIVITY;

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.