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UniProtKB/Swiss-Prot P07949: Variant p.Cys634Arg

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

Variant position:  634
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 Arginine (R) at position 634 (C634R, p.Cys634Arg).
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 basic (R)
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:  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.

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:  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.

Variant description:  In MEN2A, pheochromocytoma and MTC; familial form; also found as somatic mutation in a sporadic thyroid carcinoma.
Any additional useful information about the variant.

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



Sequence information

Variant position:  634
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:   EEEKCFCEPEDIQDPLCDEL  C RTVIAAAVLFSFIVSVLLSA
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                         EEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSA

Mouse                         DEKKCFCEPEDSQGPLCDALCRTIITAA-LFSLIISILLSI

Rat                           DEKKCFCEPEDSQGPLCDELCRTVITAAVLFSFIISVLLST

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 29 – 707 Extracellular cell-membrane anchored RET cadherin 120 kDa fragment
Topological domain 29 – 635 Extracellular


Literature citations

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
Donis-Keller H.; Dou S.; Chi D.; Carlson K.M.; Toshima K.; Lairmore T.C.; Howe J.R.; Moley J.F.; Goodfellow P.; Wells S.A. Jr.;
Hum. Mol. Genet. 2:851-856(1993)
Cited for: VARIANTS MEN2A/MTC TRP-611; SER-618; ARG-620; TYR-620 AND ARG-634;

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
Mulligan L.M.; Kwok J.B.J.; Healey C.S.; Elsdon M.J.; Eng C.; Gardner E.; Love D.R.; Mole S.E.; Moore J.K.; Papi L.; Ponder M.A.; Telenius H.; Tunnacliffe A.; Ponder B.A.J.;
Nature 363:458-460(1993)
Cited for: VARIANTS MEN2A GLY-618; 632-ASP--ARG-634; GLY-634; PHE-634; TYR-634 AND SER-634;

Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A).
Takiguchi-Shirahama S.; Koyama K.; Miyauchi A.; Wakasugi T.; Oishi S.; Takami H.; Hikiji K.; Nakamura Y.;
Hum. Genet. 95:187-190(1995)
Cited for: VARIANTS MEN2A SER-618; SER-620; ARG-634 AND TYR-634;

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.