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UniProtKB/Swiss-Prot P16473: Variant p.Cys390Trp

Thyrotropin receptor
Gene: TSHR
Variant information

Variant position:  390
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 Cysteine (C) to Tryptophan (W) at position 390 (C390W, p.Cys390Trp).
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 (C) to large size and aromatic (W)
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:  Hypothyroidism, congenital, non-goitrous, 1 (CHNG1) [MIM:275200]: A non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. It presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland. {ECO:0000269|PubMed:10720030, ECO:0000269|PubMed:11095460, ECO:0000269|PubMed:11442002, ECO:0000269|PubMed:12050212, ECO:0000269|PubMed:14725684, ECO:0000269|PubMed:15531543, ECO:0000269|PubMed:25978107, ECO:0000269|PubMed:7528344, ECO:0000269|PubMed:8954020, ECO:0000269|PubMed:9100579, ECO:0000269|PubMed:9185526, ECO:0000269|PubMed:9329388}. 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 CHNG1; persistent hypothyroidism and defective thyroid development; abolishes high affinity hormone binding.
Any additional useful information about the variant.

Sequence information

Variant position:  390
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  764
The length of the canonical sequence.

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.









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.

Chain 21 – 764 Thyrotropin receptor
Topological domain 21 – 413 Extracellular
Modified residue 385 – 385 Sulfotyrosine
Alternative sequence 254 – 764 Missing. In isoform Short.
Alternative sequence 275 – 764 Missing. In isoform 3.
Mutagenesis 385 – 385 Y -> E. Reduces binding with thyrotropin. Inhibits intracellular cAMP accumulation.
Mutagenesis 385 – 385 Y -> F. Reduces sulfation. Reduces binding with thyrotropin. Inhibits intracellular cAMP accumulation.
Mutagenesis 387 – 387 Y -> E. No change in intracellular cAMP accumulation.
Mutagenesis 387 – 387 Y -> F. Reduces sulfation. No change in intracellular cAMP accumulation.

Literature citations

Four families with loss of function mutations of the thyrotropin receptor.
de Roux N.; Misrahi M.; Brauner R.; Houang M.; Carel J.-C.; Granier M.; Le Bouc Y.; Ghinea N.; Boumedienne A.; Toublanc J.E.; Milgrom E.;
J. Clin. Endocrinol. Metab. 81:4229-4235(1996)
Cited for: VARIANTS CHNG1 SER-41; ALA-162; TRP-390; ASN-410 AND LEU-525;

Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism.
Biebermann H.; Schoeneberg T.; Krude H.; Schultz G.; Gudermann T.; Grueters A.;
J. Clin. Endocrinol. Metab. 82:3471-3480(1997)
Cited for: VARIANT CHNG1 TRP-390;

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.