UniProtKB/Swiss-Prot P06213: Variant p.Pro997Thr

Insulin receptor
Gene: INSR
Chromosomal location: 19p13.2-p13.3
Variant information

Variant position:  997
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 Proline (P) to Threonine (T) at position 997 (P997T, p.Pro997Thr).
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 hydrophobic (P) to medium size and polar (T)
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

Involvement in disease:  Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10443650, ECO:0000269|PubMed:12023989, ECO:0000269|PubMed:17201797, ECO:0000269|PubMed:2121734, ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:8314008}. 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 RMS; reduces insulin binding.
Any additional useful information about the variant.



Sequence information

Variant position:  997
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1382
The length of the canonical sequence.

Location on the sequence:   LFLRKRQPDGPLGPLYASSN  P EYLSASDVFPCSVYVPDEWE
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                         LFLRKRQ-PDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWE

Mouse                         LFLRKRQ-PDGPMGPLYASSNPEYLSASDVFPSSVYVPDEW

Rat                           LFLRKRQ-PDGPMGPLYASSNPEYLSASDVFPSSVYVPDEW

Xenopus laevis                CVVQKKKDAEGPAGPLYTSSNPEYLSASE-----VYIPDEW

Caenorhabditis elegans        YYIQVRYGKKVKALSDFMQLNPEYCVDN------KYNADDW

Drosophila                    CYLHKRKVPSNDL-HMNTEVNPFYASM-------QYIPDDW

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 763 – 1382 Insulin receptor subunit beta
Topological domain 980 – 1382 Cytoplasmic
Region 999 – 999 Important for interaction with IRS1, SHC1 and STAT5B
Modified residue 992 – 992 Phosphotyrosine; by autocatalysis
Modified residue 999 – 999 Phosphotyrosine; by autocatalysis
Modified residue 1011 – 1011 Phosphotyrosine; by autocatalysis
Mutagenesis 991 – 991 L -> A. Reduces interaction with IRS1 but has no effect on interaction with SHC1.
Mutagenesis 992 – 992 Y -> A. Reduces interaction with IRS1 but has no effect on interaction with SHC1.
Mutagenesis 996 – 997 NP -> AA. Abolishes interaction with IRS1. Severely disrupts, but does not abolish interaction with SHC1.
Mutagenesis 996 – 996 N -> A. Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1.
Mutagenesis 997 – 997 P -> A. Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1.
Mutagenesis 998 – 998 E -> A. Does not affect interaction with IRS1, SHC1 or PIK3R1.
Mutagenesis 999 – 999 Y -> E. Abolishes interaction with IRS1 and SHC1.
Mutagenesis 999 – 999 Y -> F. Has no effect on insulin-stimulated autophosphorylation, but inhibits the biological activity of the receptor. Abolishes interaction with IRS1 and almost completely prevents interaction with SHC1. Has no effect on interaction with PIK3R1. Abolishes interaction with STAT5B.
Mutagenesis 1000 – 1000 L -> AR. Severely reduces interaction with SHC1. Has no effect on interaction with IRS1.
Mutagenesis 1002 – 1002 A -> D. Reduces interaction with IRS1 but has no effect on interaction with SHC1.
Mutagenesis 1011 – 1011 Y -> A. Increases kinase activity.


Literature citations

Genotype-phenotype correlation in inherited severe insulin resistance.
Longo N.; Wang Y.; Smith S.A.; Langley S.D.; DiMeglio L.A.; Giannella-Neto D.;
Hum. Mol. Genet. 11:1465-1475(2002)
Cited for: CHARACTERIZATION OF VARIANTS LEPRCH PRO-113; VAL-119; ASN-308 DEL; THR-925 AND TRP-926; VARIANTS RMS THR-997; THR-1143; TRP-1158 AND TRP-1201;

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.