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UniProtKB/Swiss-Prot P07949: Variant p.Tyr791Phe

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

Variant position:  791
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 Tyrosine (Y) to Phenylalanine (F) at position 791 (Y791F, p.Tyr791Phe).
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 large size and aromatic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  3
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:  Hirschsprung disease 1 (HSCR1) [MIM:142623]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. {ECO:0000269|PubMed:10090908, ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407, ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377, ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870, ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613, ECO:0000269|Ref.62}. 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.

Involvement in disease:  Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520, ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092, ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675, ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735, ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724, ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. 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.

Involvement in disease:  Pheochromocytoma (PCC) [MIM:171300]: A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease susceptibility is associated with variations 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.

Involvement in disease:  Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. {ECO:0000269|PubMed:10522989, ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613, ECO:0000269|PubMed:9452064}. 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 HSCR1, pheochromocytoma, MTC and MEN2A; familial form.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  791
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:   DLLSEFNVLKQVNHPHVIKL  Y GACSQDGPLLLIVEYAKYGS
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                         DLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGS

Mouse                         DLLSEFNLLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGS

Rat                           DLLSEFNLLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGS

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 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 806 – 806 Phosphotyrosine; by autocatalysis
Modified residue 809 – 809 Phosphotyrosine; by autocatalysis
Mutagenesis 708 – 1114 Missing. Loss of induced cell death, but increased cell aggregation.
Beta strand 790 – 794


Literature citations

Frequency of RET mutations in long- and short-segment Hirschsprung disease.
Seri M.; Yin L.; Barone V.; Bolino A.; Celli I.; Bocciardi R.; Pasini B.; Ceccherini I.; Lerone M.; Kristoffersson U.; Larsson L.T.; Casasa J.M.; Cass D.T.; Abramowicz M.J.; Vanderwinden J.-M.; Kravcenkiene I.; Baric I.; Silengo M.; Martucciello G.; Romeo G.;
Hum. Mutat. 9:243-249(1997)
Cited for: VARIANTS HSCR1 PRO-180; GLN-313; ARG-620 AND PHE-791;

A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.
Berndt I.; Reuter M.; Saller B.; Frank-Raue K.; Groth P.; Grussendorf M.; Raue F.; Ritter M.M.; Hoeppner W.;
J. Clin. Endocrinol. Metab. 83:770-774(1998)
Cited for: VARIANTS MTC/MEN2A PHE-790 AND PHE-791;

Germ-line mutations in nonsyndromic pheochromocytoma.
Neumann H.P.H.; Bausch B.; McWhinney S.R.; Bender B.U.; Gimm O.; Franke G.; Schipper J.; Klisch J.; Altehoefer C.; Zerres K.; Januszewicz A.; Smith W.M.; Munk R.; Manz T.; Glaesker S.; Apel T.W.; Treier M.; Reineke M.; Walz M.K.; Hoang-Vu C.; Brauckhoff M.; Klein-Franke A.; Klose P.; Schmidt H.; Maier-Woelfle M.; Peczkowska M.; Szmigielski C.; Eng C.;
N. Engl. J. Med. 346:1459-1466(2002)
Cited for: VARIANTS PHEOCHROMOCYTOMA ARG-634; GLY-634; TYR-634; SER-634; PHE-634; TRP-634 AND PHE-791;

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.