UniProtKB/Swiss-Prot P07949: Variant p.Met918Thr

Proto-oncogene tyrosine-protein kinase receptor Ret
Gene: RET
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Variant information Variant position:

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

LP/P [Disclaimer] 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 Methionine (M) to Threonine (T) at position 918 (M918T, p.Met918Thr). 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 (M) 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
Variant description:

In MEN2B and MTC; sporadic form; somatic mutation; also found in a patient with renal agenesis; faster autophosphorylation and activation, leading to enhanced activity. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs74799832 [ dbSNP | Ensembl ]

Sequence information Variant position:

918 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

1114 The length of the canonical sequence.
Location on the sequence:

DVYEEDSYVKRSQGRIPVKW M AIESLFDHIYTTQSDVWSFG 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                         DVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFG

Mouse                         DVYEEDSYVKKSKGRIPVKWMAIESLFDHIYTTQSDVWSFG

Rat                           DVYEEDSYVKKSKGRIPVKWMAIESLFDHIYTTQSDVWSFG

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	29 – 1114	Proto-oncogene tyrosine-protein kinase receptor Ret
Chain	708 – 1017	Soluble RET kinase fragment
Topological domain	658 – 1114	Cytoplasmic
Domain	724 – 1016	Protein kinase
Modified residue	900 – 900	Phosphotyrosine; by autocatalysis
Modified residue	905 – 905	Phosphotyrosine; by autocatalysis
Mutagenesis	708 – 1114	Missing. Loss of induced cell death, but increased cell aggregation.
Mutagenesis	912 – 912	R -> A. Enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
Mutagenesis	913 – 913	I -> A. Enhanced protein autophosphorylation due to enhanced substrate presentation in trans.

Literature citations
Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans.
Plaza-Menacho I.; Barnouin K.; Goodman K.; Martinez-Torres R.J.; Borg A.; Murray-Rust J.; Mouilleron S.; Knowles P.; McDonald N.Q.;
Mol. Cell 53:738-751(2014)
Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 705-1013 IN COMPLEX WITH ADENOSINE; FUNCTION; CATALYTIC ACTIVITY; PHOSPHORYLATION AT TYR-687; TYR-826; TYR-900; TYR-905; TYR-981; TYR-1015; TYR-1029 AND TYR-1062; MUTAGENESIS OF GLU-734; LYS-758; ARG-912 AND ILE-913; VARIANT MEN2B THR-918; CHARACTERIZATION OF VARIANT MEN2B THR-918; VARIANT MTC MET-804; CHARACTERIZATION OF VARIANT MTC MET-804; Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.
Eng C.; Smith D.P.; Mulligan L.M.; Nagai M.A.; Healey C.S.; Ponder M.A.; Gardner E.; Scheumann G.F.; Jackson C.E.; Tunnacliffe A.; Ponder B.A.J.;
Hum. Mol. Genet. 3:237-241(1994)
Cited for: VARIANT MEN2B THR-918; A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
Hofstra R.M.W.; Landsvater R.M.; Ceccherini I.; Stulp R.P.; Stelwagen T.; Luo Y.; Pasini B.; Hoeppener J.W.M.; Ploos van Amstel H.K.; Romeo G.; Lips C.J.M.; Buys C.H.C.M.;
Nature 367:375-376(1994)
Cited for: VARIANT MEN2B THR-918; Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.
Carlson K.M.; Dou S.; Chi D.; Scavarda N.; Toshima K.; Jackson C.E.; Wells S.A. Jr.; Goodfellow P.J.; Donis-Keller H.;
Proc. Natl. Acad. Sci. U.S.A. 91:1579-1583(1994)
Cited for: VARIANT MEN2B THR-918; Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B.
Kitamura Y.; Scavarda N.; Wells S.A. Jr.; Jackson C.E.; Goodfellow P.J.;
Hum. Mol. Genet. 4:1987-1988(1995)
Cited for: VARIANT MEN2B THR-918; VARIANT TYR-922; Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations.
Kambouris M.; Jackson C.E.; Feldman G.L.;
Hum. Mutat. 8:64-70(1996)
Cited for: VARIANTS MEN2A; VARIANT MTC ASP-768; VARIANT MEN2B THR-918; Renal aplasia in humans is associated with RET mutations.
Skinner M.A.; Safford S.D.; Reeves J.G.; Jackson M.E.; Freemerman A.J.;
Am. J. Hum. Genet. 82:344-351(2008)
Cited for: VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; THR-918; LEU-1049 AND SER-1067; POSSIBLE INVOLVEMENT IN RENAL AGENESIS; CHARACTERIZATION OF VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; LEU-1049 AND SER-1067; Drug resistance profiles of mutations in the RET kinase domain.
Liu X.; Shen T.; Mooers B.H.M.; Hilberg F.; Wu J.;
Br. J. Pharmacol. 175:3504-3515(2018)
Cited for: ACTIVITY REGULATION; VARIANTS ILE-730; VAL-730; LYS-732; ALA-738; ASN-806; VAL-807; ALA-810; SER-810; ILE-871 AND VAL-998; CHARACTERIZATION OF VARIANTS ILE-730; VAL-730; LYS-732; ALA-738; ASN-806; VAL-807; ALA-810; SER-810; ILE-871 AND VAL-998; VARIANTS MTC LEU-804; MET-804 AND THR-918; CHARACTERIZATION OF VARIANTS MTC LEU-804; MET-804 AND THR-918;

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.