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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P16473: Variant p.Asp727Glu

Thyrotropin receptor
Gene: TSHR
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Variant information Variant position: help 727 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant: help 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: help From Aspartate (D) to Glutamate (E) at position 727 (D727E, p.Asp727Glu). 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: help Similar physico-chemical property. Both residues are medium size and acidic. The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score: help 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

Polymorphism: help The Asp727Glu polymorphism is associated with Graves disease in a Russian population. The Glu727 allele and the heterozygous Asp727Glu genotype are related to higher risk of the disease. The Asp727Glu polymorphism significantly ameliorates G(s)alpha protein activation in the presence of the gain-of-function mutation Ala593Asn although it is functionally inert in the context of the wild-type TSHR. Additional information on the polymorphism described.
Variant description: help May be a predisposing factor in toxic multinodular goiter pathogenesis; activation of the cAMP cascade does not differ from the wild-type. Any additional useful information about the variant.
Other resources: help Links to websites of interest for the variant.


Sequence information Variant position: help 727 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length: help 764 The length of the canonical sequence.
Location on the sequence: help RGQRVPPKNSTDIQVQKVTH D MRQGLHNMEDVYELIENSHL 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: help The multiple alignment of the region surrounding the variant against various orthologous sequences.
Human                         RGQRVPPKNSTDIQVQKVTHDMRQGLHNMEDVYELIENSHL

                              RGQRVSPKNSAGIQIQKVTRDMRQSLPNMQDEYELLENSHL

Mouse                         QGQRVCPNNSTGIQIQKIPQDTRQSLPNMQDTYELLGNSQL

Rat                           QAQRVCPNNNTGIQIQKIPQDTRQSLPNVQDTYEPLGSSHL

Pig                           RGQRVSPKNSTGIQVQKVTQNMRQSLPNMQDDYELLENSHL

Bovine                        RGQRVSPKNSTGIRVQKVPPDVRQSLPNVQDDYELLENSHL

Sheep                         RGQRVSSKNSTGIRVQKVPPDVRQSLPNVQDDYELLGNSHL

Cat                           RGQRVSPKNSTGIQVQKVTRNMRQSLPNMQDDYELLENSHL

Sequence annotation in neighborhood: help 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 21 – 764 Thyrotropin receptor
Topological domain 683 – 764 Cytoplasmic
Alternative sequence 254 – 764 Missing. In isoform Short.
Alternative sequence 275 – 764 Missing. In isoform 3.



Literature citations
Cloning, sequencing and expression of human TSH receptor.
Misrahi M.; Loosfelt H.; Atger M.; Sar S.; Guiochon-Mantel A.; Milgrom E.;
Biochem. Biophys. Res. Commun. 166:394-403(1990)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG); VARIANT GLU-727; The DNA sequence and analysis of human chromosome 14.
Heilig R.; Eckenberg R.; Petit J.-L.; Fonknechten N.; Da Silva C.; Cattolico L.; Levy M.; Barbe V.; De Berardinis V.; Ureta-Vidal A.; Pelletier E.; Vico V.; Anthouard V.; Rowen L.; Madan A.; Qin S.; Sun H.; Du H.; Pepin K.; Artiguenave F.; Robert C.; Cruaud C.; Bruels T.; Jaillon O.; Friedlander L.; Samson G.; Brottier P.; Cure S.; Segurens B.; Aniere F.; Samain S.; Crespeau H.; Abbasi N.; Aiach N.; Boscus D.; Dickhoff R.; Dors M.; Dubois I.; Friedman C.; Gouyvenoux M.; James R.; Madan A.; Mairey-Estrada B.; Mangenot S.; Martins N.; Menard M.; Oztas S.; Ratcliffe A.; Shaffer T.; Trask B.; Vacherie B.; Bellemere C.; Belser C.; Besnard-Gonnet M.; Bartol-Mavel D.; Boutard M.; Briez-Silla S.; Combette S.; Dufosse-Laurent V.; Ferron C.; Lechaplais C.; Louesse C.; Muselet D.; Magdelenat G.; Pateau E.; Petit E.; Sirvain-Trukniewicz P.; Trybou A.; Vega-Czarny N.; Bataille E.; Bluet E.; Bordelais I.; Dubois M.; Dumont C.; Guerin T.; Haffray S.; Hammadi R.; Muanga J.; Pellouin V.; Robert D.; Wunderle E.; Gauguet G.; Roy A.; Sainte-Marthe L.; Verdier J.; Verdier-Discala C.; Hillier L.W.; Fulton L.; McPherson J.; Matsuda F.; Wilson R.; Scarpelli C.; Gyapay G.; Wincker P.; Saurin W.; Quetier F.; Waterston R.; Hood L.; Weissenbach J.;
Nature 421:601-607(2003)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]; VARIANT GLU-727; Further studies of genetic susceptibility to Graves' disease in a Russian population.
Chistiakov D.A.; Savost'anov K.V.; Turakulov R.I.; Petunina N.; Balabolkin M.I.; Nosikov V.V.;
Med. Sci. Monit. 8:CR180-CR184(2002)
Cited for: ANALYSIS OF INVOLVEMENT OF VARIANT GLU-727 IN GRAVES DISEASE; A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease.
Ban Y.; Greenberg D.A.; Concepcion E.S.; Tomer Y.;
Thyroid 12:1079-1083(2002)
Cited for: ANALYSIS OF INVOLVEMENT OF VARIANT GLU-727 IN GRAVES DISEASE; Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins.
Ho S.-C.; Goh S.-S.; Khoo D.H.;
Thyroid 13:523-528(2003)
Cited for: ANALYSIS OF INVOLVEMENT OF VARIANTS HIS-36; THR-52 AND GLU-727 IN GRAVES DISEASE; Point mutations in the thyrotropin receptor in human thyroid tumors.
Ohno M.; Endo T.; Ohta K.; Gunji K.; Onaya T.;
Thyroid 5:97-100(1995)
Cited for: VARIANTS PAPILLARY CANCER ILE-197; GLU-219; ASP-715 AND MET-723; VARIANT GLU-727; Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter.
Gabriel E.M.; Bergert E.R.; Grant C.S.; van Heerden J.A.; Thompson G.B.; Morris J.C.;
J. Clin. Endocrinol. Metab. 84:3328-3335(1999)
Cited for: VARIANTS MET-606; GLY-703; GLU-720 AND GLU-727; Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population.
Muehlberg T.; Herrmann K.; Joba W.; Kirchberger M.; Heberling H.-J.; Heufelder A.E.;
J. Clin. Endocrinol. Metab. 85:2640-2643(2000)
Cited for: VARIANT GLU-727; Functional significance of the thyrotropin receptor germline polymorphism D727E.
Sykiotis G.P.; Neumann S.; Georgopoulos N.A.; Sgourou A.; Papachatzopoulou A.; Markou K.B.; Kyriazopoulou V.; Paschke R.; Vagenakis A.G.; Papavassiliou A.G.;
Biochem. Biophys. Res. Commun. 301:1051-1056(2003)
Cited for: VARIANT TOXIC THYROID ADENOMA ASN-593; VARIANT GLU-727; CHARACTERIZATION OF VARIANT TOXIC THYROID ADENOMA ASN-593; CHARACTERIZATION OF VARIANT GLU-727; Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects.
Peeters R.P.; van Toor H.; Klootwijk W.; de Rijke Y.B.; Kuiper G.G.J.M.; Uitterlinden A.G.; Visser T.J.;
J. Clin. Endocrinol. Metab. 88:2880-2888(2003)
Cited for: VARIANTS HIS-36; THR-52 AND GLU-727; ASSOCIATION WITH PLASMA TSH LEVEL;
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.