UniProtKB/Swiss-Prot Q12879: Variant p.Met653Ile

Glutamate receptor ionotropic, NMDA 2A
Gene: GRIN2A
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Variant information Variant position:

653 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 Methionine (M) to Isoleucine (I) at position 653 (M653I, p.Met653Ile). 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:

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
Variant description:

In FESD; likely pathogenic; also found in a cutaneous malignant melanoma sample; somatic mutation; controversial results on functional consequences; decreased localization to cell membrane according to PubMed:38538865; unchanged localization to cell membrane according to PubMed:38307912; increased agonist potency and channel activation at lower glutamate and glycine concentrations compared to wild type channels according to PubMed:38538865; loss of function in ion transmembrane transport and lack of channel activation by glutamate according to PubMed:38307912. Any additional useful information about the variant.

Sequence information Variant position:

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

1464 The length of the canonical sequence.
Location on the sequence:

VWAFFAVIFLASYTANLAAF M IQEEFVDQVTGLSDKKFQRP 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                         VWAFFAVIFLASYTANLAAFMIQEEFVDQVTGLSDKKFQRP

Chimpanzee                    VWAFFAVIFLASYTANLAAFMIQEEFVDQVTGLSDKKFQRP

Mouse                         VWAFFAVIFLASYTANLAAFMIQEEFVDQVTGLSDKKFQRP

Rat                           VWAFFAVIFLASYTANLAAFMIQEEFVDQVTGLSDKKFQRP

Xenopus laevis                IWAFFAVIFLASYTANLAAFMIQEEFVDQVTGLSDNKFQRP

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	23 – 1464	Glutamate receptor ionotropic, NMDA 2A
Topological domain	647 – 814	Extracellular
Mutagenesis	646 – 646	T -> R. No effect on localization to the cell membrane. Results in increased glycine potency and channel activation at lower agonist concentrations.
Helix	625 – 654

Literature citations
Exome sequencing identifies GRIN2A as frequently mutated in melanoma.
Wei X.; Walia V.; Lin J.C.; Teer J.K.; Prickett T.D.; Gartner J.; Davis S.; Stemke-Hale K.; Davies M.A.; Gershenwald J.E.; Robinson W.; Robinson S.; Rosenberg S.A.; Samuels Y.;
Nat. Genet. 43:442-446(2011)
Cited for: PROBABLE INVOLVEMENT IN MELANOMA; VARIANTS LEU-57; ILE-183; ASN-252; PHE-278; LYS-371; LYS-373; GLU-449; SER-459; ARG-595; PHE-598; ILE-653; GLU-712; TRP-740; GLU-889; LYS-920; PHE-929; LYS-962; LYS-1073; LEU-1074; ASN-1153; LYS-1175; GLY-1276; LYS-1285; TRP-1318; LEU-1366; ASN-1421; LEU-1425; LYS-1426 AND CYS-1462; GRIN2A-related disorders: genotype and functional consequence predict phenotype.
Strehlow V.; Heyne H.O.; Vlaskamp D.R.M.; Marwick K.F.M.; Rudolf G.; de Bellescize J.; Biskup S.; Brilstra E.H.; Brouwer O.F.; Callenbach P.M.C.; Hentschel J.; Hirsch E.; Kind P.C.; Mignot C.; Platzer K.; Rump P.; Skehel P.A.; Wyllie D.J.A.; Hardingham G.E.; van Ravenswaaij-Arts C.M.A.; Lesca G.; Lemke J.R.;
Brain 142:80-92(2019)
Cited for: VARIANTS FESD GLN-411; SER-498; CYS-518; VAL-532; GLN-611; SER-614; THR-635; GLY-644; SER-648; VAL-649; PRO-649; ILE-653; THR-654; ALA-684; GLN-695; GLY-713; THR-716; ASN-731; THR-733; ARG-809; VAL-817 AND GLU-818; De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.
Xu Y.; Song R.; Perszyk R.E.; Chen W.; Kim S.; Park K.L.; Allen J.P.; Nocilla K.A.; Zhang J.; Xiang Wei W.; Tankovic A.; McDaniels E.D.; Sheikh R.; Mizu R.K.; Karamchandani M.M.; Hu C.; Kusumoto H.; Pecha J.; Cappuccio G.; Gaitanis J.; Sullivan J.; Shashi V.; Petrovski S.; Jauss R.T.; Lee H.K.; Bozarth X.; Lynch D.R.; Helbig I.; Pierson T.M.; Boerkoel C.F.; Myers S.J.; Lemke J.R.; Benke T.A.; Yuan H.; Traynelis S.F.;
Cell. Mol. Life Sci. 81:153-153(2024)
Cited for: VARIANTS FESD THR-635; ILE-639; ARG-642; ALA-646; SER-648; SER-650; VAL-652 AND VAL-653; CHARACTERIZATION OF VARIANTS FESD THR-635; ILE-639; ARG-642; GLY-644; ALA-646; SER-648; VAL-649; SER-650; ILE-653; VAL-653 AND THR-654; VARIANT MET-642; CHARACTERIZATION OF VARIANTS MET-642 AND ASP-643; MUTAGENESIS OF SER-632 AND THR-646; FUNCTION; TRANSPORTER ACTIVITY; ACTIVITY REGULATION; SUBCELLULAR LOCATION; Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders.
Shepard N.; Baez-Nieto D.; Iqbal S.; Kurganov E.; Budnik N.; Campbell A.J.; Pan J.Q.; Sheng M.; Farsi Z.;
Sci. Rep. 14:2798-2798(2024)
Cited for: CHARACTERIZATION OF VARIANTS 58-GLU--GLU-1461 DEL; LEU-576; LYS-586; ARG-591; MET-605; ILE-653; HIS-671; CYS-698; 700-TYR--VAL-1464 DEL; ARG-707; VAL-727; THR-727; MET-775; ALA-784; ILE-788; MET-794; ARG-809; PRO-811; MET-812; LEU-967; THR-1295 AND 1339-LYS--VAL-1464 DEL; FUNCTION;

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.