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UniProtKB/Swiss-Prot P02766: Variant p.Val50Met

Transthyretin
Gene: TTR
Variant information

Variant position:  50
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 Valine (V) to Methionine (M) at position 50 (V50M, p.Val50Met).
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

Involvement in disease:  Amyloidosis, transthyretin-related (AMYL-TTR) [MIM:105210]: A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor. {ECO:0000269|PubMed:10036587, ECO:0000269|PubMed:10071047, ECO:0000269|PubMed:10211412, ECO:0000269|PubMed:10436378, ECO:0000269|PubMed:10439117, ECO:0000269|PubMed:10611950, ECO:0000269|PubMed:10627135, ECO:0000269|PubMed:10694917, ECO:0000269|PubMed:10842705, ECO:0000269|PubMed:10842718, ECO:0000269|PubMed:10882995, ECO:0000269|PubMed:11243784, ECO:0000269|PubMed:11445644, ECO:0000269|PubMed:11866053, ECO:0000269|PubMed:12050338, ECO:0000269|PubMed:12403615, ECO:0000269|PubMed:12557757, ECO:0000269|PubMed:12771253, ECO:0000269|PubMed:1301926, ECO:0000269|PubMed:1351039, ECO:0000269|PubMed:1362222, ECO:0000269|PubMed:1436517, ECO:0000269|PubMed:1517749, ECO:0000269|PubMed:1520326, ECO:0000269|PubMed:1520336, ECO:0000269|PubMed:15214015, ECO:0000269|PubMed:15217993, ECO:0000269|PubMed:1544214, ECO:0000269|PubMed:15478468, ECO:0000269|PubMed:1570831, ECO:0000269|PubMed:15735344, ECO:0000269|PubMed:16185074, ECO:0000269|PubMed:1656975, ECO:0000269|PubMed:16627944, ECO:0000269|PubMed:1734866, ECO:0000269|PubMed:17453626, ECO:0000269|PubMed:17503405, ECO:0000269|PubMed:17577687, ECO:0000269|PubMed:17635579, ECO:0000269|PubMed:19167329, ECO:0000269|PubMed:1932142, ECO:0000269|PubMed:2046936, ECO:0000269|PubMed:2161654, ECO:0000269|PubMed:23317988, ECO:0000269|PubMed:2363717, ECO:0000269|PubMed:2891727, ECO:0000269|PubMed:3022108, ECO:0000269|PubMed:3135807, ECO:0000269|PubMed:3722385, ECO:0000269|PubMed:3818577, ECO:0000269|PubMed:6487335, ECO:0000269|PubMed:6583672, ECO:0000269|PubMed:6651852, ECO:0000269|PubMed:7655883, ECO:0000269|PubMed:7850982, ECO:0000269|PubMed:7910950, ECO:0000269|PubMed:7914929, ECO:0000269|PubMed:7923855, ECO:0000269|PubMed:8019560, ECO:0000269|PubMed:8038017, ECO:0000269|PubMed:8081397, ECO:0000269|PubMed:8095302, ECO:0000269|PubMed:8133316, ECO:0000269|PubMed:8257997, ECO:0000269|PubMed:8352764, ECO:0000269|PubMed:8382610, ECO:0000269|PubMed:8428915, ECO:0000269|PubMed:8579098, ECO:0000269|PubMed:8990019, ECO:0000269|PubMed:9066351, ECO:0000269|PubMed:9605286, ECO:0000269|PubMed:9733771, ECO:0000269|Ref.90}. 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 AMYL-TTR; amyloid polyneuropathy; by far the most frequent mutation.
Any additional useful information about the variant.

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



Sequence information

Variant position:  50
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  147
The length of the canonical sequence.

Location on the sequence:   CPLMVKVLDAVRGSPAINVA  V HVFRKAADDTWEPFASGKTS
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                         CPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTS

Chimpanzee                    CPLMVKVLDAVRGSPAINVAVHVFKKAADETWEPFASGKTS

Mouse                         CPLMVKVLDAVRGSPAVDVAVKVFKKTSEGSWEPFASGKTA

Rat                           CPLMVKVLDAVRGSPAVDVAVKVFKKTADGSWEPFASGKTA

Pig                           CPLMVKVLDAVRGSPAVNVGVKVFKKAADGTWEPFALGKTS

Bovine                        CPLMVKVLDAVRGSPAANVGVKVFKKAADETWEPFASGKTS

Rabbit                        CPLMVKVLDAVRGSPAVDVSVHVFKKAADETWEPFASGKTS

Sheep                         CPLMVKVLDAVRGSPAANVGVKVFKKAADETWEPFASGKTS

Chicken                       CPLMVKVLDAVRGSPAANVAVKVFKKAADGTWQDFATGKTT

Xenopus laevis                CPLMVKVLDAVRGIPAANLLVNVFRQTESGKWEQITSGKTT

Xenopus tropicalis            CPLMVKVLDAVRGIPAANLLVQVFRNT-EGNWELISSGKTT

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 21 – 147 Transthyretin
Binding site 35 – 35 Thyroid hormones
Modified residue 62 – 62 4-carboxyglutamate; in a patient with Moyamoya disease
Beta strand 49 – 55


Literature citations

Analyses of prealbumin mRNAs in individuals with familial amyloidotic polyneuropathy.
Mita S.; Maeda S.; Shimada K.; Araki S.;
J. Biochem. 100:1215-1222(1986)
Cited for: NUCLEOTIDE SEQUENCE [MRNA]; VARIANT AMYL-TTR MET-50;

Structure and expression of the mutant prealbumin gene associated with familial amyloidotic polyneuropathy.
Maeda S.; Mita S.; Araki S.; Shimada K.;
Mol. Biol. Med. 3:329-338(1986)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANT AMYL-TTR MET-50;

Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type).
Tawara S.; Nakazato M.; Kangawa K.; Matsuo H.; Araki S.;
Biochem. Biophys. Res. Commun. 116:880-888(1983)
Cited for: PROTEIN SEQUENCE OF 21-147; VARIANT AMYL-TTR MET-50;

Primary structure of an amyloid prealbumin and its plasma precursor in a heredofamilial polyneuropathy of Swedish origin.
Dwulet F.E.; Benson M.D.;
Proc. Natl. Acad. Sci. U.S.A. 81:694-698(1984)
Cited for: PROTEIN SEQUENCE OF 21-147; VARIANT AMYL-TTR MET-50;

Characterization of a transthyretin-related amyloid fibril protein from cerebral amyloid angiopathy in type I familial amyloid polyneuropathy.
Kametani F.; Ikeda S.; Yanagisawa N.; Ishi T.; Hanyu N.;
J. Neurol. Sci. 108:178-183(1992)
Cited for: PROTEIN SEQUENCE OF 21-147; VARIANT AMYL-TTR MET-50;

Structure of Met30 variant of transthyretin and its amyloidogenic implications.
Terry C.J.; Damas A.M.; Oliveira P.; Saraiva M.J.M.; Alves I.L.; Costa P.P.; Matias P.M.; Sakaki Y.; Blake C.C.F.;
EMBO J. 12:735-741(1993)
Cited for: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF VARIANT AMYL-TTR MET-50;

The X-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution.
Hamilton J.A.; Steinrauf L.K.; Braden B.C.; Liepnieks J.; Benson M.D.; Holmgren G.; Sandgren O.; Steen L.;
J. Biol. Chem. 268:2416-2424(1993)
Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF VARIANT AMYL-TTR MET-50;

Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution.
Sebastiao M.P.; Lamzin V.; Saraiva M.J.; Damas A.M.;
J. Mol. Biol. 306:733-744(2001)
Cited for: X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS) OF 30-144 OF VARIANT AMYL-TTR MET-50 AND VARIANT CHICAGO MET-139 IN COMPLEX WITH L-THYROXINE; SUBUNIT;

Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy.
Reilly M.M.; Adams D.; Booth D.R.; Davis M.B.; Said G.; Laubriat-Bianchin M.; Pepys M.B.; Thomas P.K.; Harding A.E.;
Brain 118:849-856(1995)
Cited for: VARIANTS AMYL-TTR MET-50; ASN-55; ALA-69; ARG-70; ALA-80; TYR-97 AND GLN-109;

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.
Lachmann H.J.; Booth D.R.; Booth S.E.; Bybee A.; Gilbertson J.A.; Gillmore J.D.; Pepys M.B.; Hawkins P.N.;
N. Engl. J. Med. 346:1786-1791(2002)
Cited for: VARIANTS AMYL-TTR MET-50; LEU-53; VAL-53; VAL-58; GLU-67; ALA-80; SER-140 AND ILE-142;

Genetic microheterogeneity of human transthyretin detected by IEF.
Altland K.; Benson M.D.; Costello C.E.; Ferlini A.; Hazenberg B.P.C.; Hund E.; Kristen A.V.; Linke R.P.; Merlini G.; Salvi F.; Saraiva M.J.; Singer R.; Skinner M.; Winter P.;
Electrophoresis 28:2053-2064(2007)
Cited for: VARIANTS AMYL-TTR PRO-32; ILE-40; SER-44; ALA-50; MET-50; LEU-53; VAL-53; PRO-56; THR-65; ALA-67; ALA-69; ILE-69; ALA-80; LEU-84; LEU-88; ALA-91; TYR-97; PHE-98; SER-104; ASN-104; THR-104; ALA-114; GLY-117; ASN-126; MET-127; VAL-127; MET-131 AND ILE-142; VARIANTS ILE-33; SER-121 AND THR-129; VARIANT CHICAGO MET-139;

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.