UniProtKB/Swiss-Prot P06213: Variant p.Val1012Met

Insulin receptor
Gene: INSR
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Variant information Variant position:

1012 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

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:

From Valine (V) to Methionine (M) at position 1012 (V1012M, p.Val1012Met). 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
Other resources:

Links to websites of interest for the variant.

Variant rs1799816 [ dbSNP | Ensembl ]

Sequence information Variant position:

1012 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:

YASSNPEYLSASDVFPCSVY V PDEWEVSREKITLLRELGQG 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                         YASS--NPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQG

Mouse                         YASS--NPEYLSASDVFPSSVYVPDEWEVPREKITLLRELG

Rat                           YASS--NPEYLSASDVFPSSVYVPDEWEVPREKITLLRELG

Xenopus laevis                YTSS--NPEYLSASE-----VYIPDEWEVPRDKINLLRELG

Caenorhabditis elegans        FMQL--NPEYCVDN------KYNADDWELRQDDVVLGQQCG

Drosophila                    HMNTEVNPFYASM-------QYIPDDWEVLRENIIQLAPLG

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	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	992 – 992	Y -> A. Reduces interaction with IRS1 but has no effect on 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
Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM.
Elbein S.C.; Sorensen L.K.; Schumacher M.C.;
Diabetes 42:429-434(1993)
Cited for: VARIANT MET-1012; Patients with lipodystrophic diabetes mellitus of the Seip-Berardinelli type, express normal insulin receptors.
van der Vorm E.R.; Kuipers A.; Bonenkamp J.W.; Kleijer W.J.; van Maldergem L.; Herwig J.; Maassen J.A.;
Diabetologia 36:172-174(1993)
Cited for: VARIANT MET-1012; Molecular scanning of the insulin receptor gene in syndromes of insulin resistance.
Krook A.; Kumar S.; Laing I.; Boulton A.J.; Wass J.A.; O'Rahilly S.;
Diabetes 43:357-368(1994)
Cited for: VARIANT RMS SYNDROME LEU-350; VARIANTS IRAN TYPE A LEU-1205 AND GLN-1378; VARIANT MET-1012; The Val985Met insulin-receptor variant in the Danish Caucasian population: lack of associations with non-insulin-dependent diabetes mellitus or insulin resistance.
Hansen L.; Hansen T.; Clausen J.O.; Echwald S.M.; Urhammer S.A.; Rasmussen S.K.; Pedersen O.;
Am. J. Hum. Genet. 60:1532-1535(1997)
Cited for: VARIANT MET-1012; Patterns of somatic mutation in human cancer genomes.
Greenman C.; Stephens P.; Smith R.; Dalgliesh G.L.; Hunter C.; Bignell G.; Davies H.; Teague J.; Butler A.; Stevens C.; Edkins S.; O'Meara S.; Vastrik I.; Schmidt E.E.; Avis T.; Barthorpe S.; Bhamra G.; Buck G.; Choudhury B.; Clements J.; Cole J.; Dicks E.; Forbes S.; Gray K.; Halliday K.; Harrison R.; Hills K.; Hinton J.; Jenkinson A.; Jones D.; Menzies A.; Mironenko T.; Perry J.; Raine K.; Richardson D.; Shepherd R.; Small A.; Tofts C.; Varian J.; Webb T.; West S.; Widaa S.; Yates A.; Cahill D.P.; Louis D.N.; Goldstraw P.; Nicholson A.G.; Brasseur F.; Looijenga L.; Weber B.L.; Chiew Y.-E.; DeFazio A.; Greaves M.F.; Green A.R.; Campbell P.; Birney E.; Easton D.F.; Chenevix-Trench G.; Tan M.-H.; Khoo S.K.; Teh B.T.; Yuen S.T.; Leung S.Y.; Wooster R.; Futreal P.A.; Stratton M.R.;
Nature 446:153-158(2007)
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-228; ARG-695; SER-811; MET-1012; VAL-1065 AND ALA-1282;

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