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UniProtKB/Swiss-Prot P23415: Variant p.Gln254Glu

Glycine receptor subunit alpha-1
Gene: GLRA1
Variant information

Variant position:  254
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 Glutamine (Q) to Glutamate (E) at position 254 (Q254E, p.Gln254Glu).
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 medium size and polar (Q) to medium size and acidic (E)
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

Involvement in disease:  Hyperekplexia 1 (HKPX1) [MIM:149400]: A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. {ECO:0000269|PubMed:10514101, ECO:0000269|PubMed:24108130, ECO:0000269|PubMed:25730860, ECO:0000269|PubMed:7611730, ECO:0000269|PubMed:7881416, ECO:0000269|PubMed:7925268, ECO:0000269|PubMed:7981700, ECO:0000269|PubMed:8298642, ECO:0000269|PubMed:8571969, ECO:0000269|PubMed:8733061, ECO:0000269|PubMed:9009272, ECO:0000269|PubMed:9067762, ECO:0000269|PubMed:9920650, ECO:0000269|Ref.18}. 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 HKPX1; strongly increases sensitivity to extracellular glycine; high leak currents in the absence of glycine due to spontaneous channel opening.
Any additional useful information about the variant.



Sequence information

Variant position:  254
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  457
The length of the canonical sequence.

Location on the sequence:   KFTCIEARFHLERQMGYYLI  Q MYIPSLLIVILSWISFWINM
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                         KFTCIEARFHLERQMGYYLIQMYIPSLLIVILSWISFWINM

Mouse                         KFTCIEARFHLERQMGYYLIQMYIPSLLIVILSWISFWINM

Rat                           KFTCIEARFHLERQMGYYLIQMYIPSLLIVILSWISFWINM

Bovine                        KFTCIEARFHLERQMGYYLIQMYIPSLLIVILSWISFWINM

Zebrafish                     KFTCIEARFHLERQMGYYLIQMYIPSLLIVILSWVSFWINM

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 29 – 457 Glycine receptor subunit alpha-1
Transmembrane 251 – 272 Helical; Name=1
Metal binding 243 – 243 Zinc
Mutagenesis 243 – 243 H -> A. Strongly decreases potentiation of channel activity by Zn(2+).
Helix 249 – 254


Literature citations

Allosteric and hyperekplexic mutant phenotypes investigated on an alpha1 glycine receptor transmembrane structure.
Moraga-Cid G.; Sauguet L.; Huon C.; Malherbe L.; Girard-Blanc C.; Petres S.; Murail S.; Taly A.; Baaden M.; Delarue M.; Corringer P.J.;
Proc. Natl. Acad. Sci. U.S.A. 112:2865-2870(2015)
Cited for: X-RAY CRYSTALLOGRAPHY (3.50 ANGSTROMS) OF 246-338 AND 418-446; FUNCTION; ACTIVITY REGULATION; SUBUNIT; SUBCELLULAR LOCATION; TOPOLOGY; CHARACTERIZATION OF VARIANTS HKPX1 GLU-254; THR-278; GLN-299 AND MET-308; MUTAGENESIS OF GLY-282 AND LYS-304;

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.
Bode A.; Wood S.E.; Mullins J.G.; Keramidas A.; Cushion T.D.; Thomas R.H.; Pickrell W.O.; Drew C.J.; Masri A.; Jones E.A.; Vassallo G.; Born A.P.; Alehan F.; Aharoni S.; Bannasch G.; Bartsch M.; Kara B.; Krause A.; Karam E.G.; Matta S.; Jain V.; Mandel H.; Freilinger M.; Graham G.E.; Hobson E.; Chatfield S.; Vincent-Delorme C.; Rahme J.E.; Afawi Z.; Berkovic S.F.; Howell O.W.; Vanbellinghen J.F.; Rees M.I.; Chung S.K.; Lynch J.W.;
J. Biol. Chem. 288:33745-33759(2013)
Cited for: VARIANTS HKPX1 TRP-93; CYS-100; TRP-246; GLU-254; SER-258; PRO-319 AND ALA-424; CHARACTERIZATION OF VARIANTS HKPX1 TRP-93; CYS-100; TRP-246; GLU-254; SER-258; HIS-280; MET-308; PRO-319; ALA-424 AND HIS-450; FUNCTION; SUBCELLULAR LOCATION;

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.