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UniProtKB/Swiss-Prot P35520: Variant p.Ile278Thr

Cystathionine beta-synthase
Gene: CBS
Variant information

Variant position:  278
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 Isoleucine (I) to Threonine (T) at position 278 (I278T, p.Ile278Thr).
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 (I) 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 CBSD; mild to severe form; common mutation; decreased expression; loss of cystathionine beta-synthase activity; impaired stimulation by AdoMet and AdoHcy; severely affects homotetramer formation by promoting formation of larger aggregates.
Any additional useful information about the variant.

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



Sequence information

Variant position:  278
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  551
The length of the canonical sequence.

Location on the sequence:   GGTITGIARKLKEKCPGCRI  I GVDPEGSILAEPEELNQTEQ
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                         GGTITGIARKLKEKCPGCRIIGVDPEGSILAEPEELNQTEQ

Mouse                         GGTITGIARKLKEKCPGCKIIGVDPEGSILAEPEELNQTEQ

Rat                           GGTITGIARKLKEKCPGCKIIGVDPEGSILAEPEELNQTEQ

Rabbit                        GGTITGIARKLKEKCPGCQIIGVDPEGSILAEPEELNQTEV

Slime mold                    GGTITGIARKIKERLPNCIVVGVDPHGSILAQPESLNNTNK

Baker's yeast                 GGTISGISKYLKEQNDKIQIVGADPFGSILAQPENLNKTDI

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 1 – 551 Cystathionine beta-synthase
Mutagenesis 272 – 272 C -> A. Reduced heme content and cystathionine beta-synthase activity.
Mutagenesis 275 – 275 C -> S. Reduced heme content and cystathionine beta-synthase activity.
Beta strand 276 – 282


Literature citations

Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity.
Kozich V.; Sokolova J.; Klatovska V.; Krijt J.; Janosik M.; Jelinek K.; Kraus J.P.;
Hum. Mutat. 31:809-819(2010)
Cited for: CHARACTERIZATION OF VARIANTS CBSD LEU-49; ARG-65; ARG-78; ASN-102; VAL-114; GLN-125; LYS-144; ARG-148; TYR-165; LYS-176; ALA-180; MET-191; LYS-228; ARG-262; LYS-266; THR-278; LYS-302; ARG-305; SER-307; CYS-369; LEU-422; THR-435; GLN-439; ASN-444; LEU-466 AND SER-539; FUNCTION; CATALYTIC ACTIVITY; PATHWAY; ACTIVITY REGULATION; SUBUNIT;

Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency.
Kozich V.; Kraus J.P.;
Hum. Mutat. 1:113-123(1992)
Cited for: VARIANT CBSD THR-278;

Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria.
Hu F.L.; Gu Z.; Kozich V.; Kraus J.P.; Ramesh V.; Shih V.E.;
Hum. Mol. Genet. 2:1857-1860(1993)
Cited for: VARIANTS CBSD THR-278 AND SER-307;

A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype.
Shih V.E.; Fringer J.M.; Mandell R.; Kraus J.P.; Berry G.T.; Heidenreich R.A.; Korson M.S.; Levy H.L.; Ramesh V.;
Am. J. Hum. Genet. 57:34-39(1995)
Cited for: VARIANTS CBSD ARG-139; LYS-144 AND THR-278;

A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene.
Kruger W.D.; Cox D.R.;
Hum. Mol. Genet. 4:1155-1161(1995)
Cited for: VARIANTS CBSD MET-168; HIS-224; THR-278; SER-307; VAL-331 AND GLU-454;

Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations.
Sperandeo M.P.; Candito M.; Sebastio G.; Rolland M.O.; Turc-Carel C.; Giudicelli H.; Dellamonica P.; Andria G.;
J. Inherit. Metab. Dis. 19:351-356(1996)
Cited for: VARIANTS CBSD ARG-116; THR-278 AND LEU-290;

Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B6-nonresponsive homocystinuria.
Dawson P.A.; Cox A.J.; Emmerson B.T.; Dudman N.P.B.; Kraus J.P.; Gordon R.B.;
Eur. J. Hum. Genet. 5:15-21(1997)
Cited for: VARIANTS CBSD LYS-144; THR-278; GLU-331; MET-353 AND GLN-439;

Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria.
Kim C.E.; Gallagher P.M.; Guttormsen A.B.; Refsum H.; Ueland P.M.; Ose L.; Foelling I.; Whitehead A.S.; Tsai M.Y.; Kruger W.D.;
Hum. Mol. Genet. 6:2213-2221(1997)
Cited for: VARIANTS CBSD MET-262; LYS-266; THR-278; SER-307; ALA-320 AND CYS-369;

Analysis of CBS alleles in Czech and Slovak patients with homocystinuria: report on three novel mutations E176K, W409X and 1223 + 37 del99.
Kozich V.; Janosik M.; Sokolova J.; Oliveriusova J.; Orendac M.; Kraus J.P.; Elleder D.;
J. Inherit. Metab. Dis. 20:363-366(1997)
Cited for: VARIANTS CBSD LYS-176; THR-278 AND SER-307;

Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria.
Gallagher P.M.; Naughten E.; Hanson N.Q.; Schwichtenberg K.; Bignell M.; Yuan M.; Ward P.; Yap S.; Whitehead A.S.; Tsai M.Y.;
Mol. Genet. Metab. 65:298-302(1998)
Cited for: VARIANTS CBSD PRO-101; LYS-228; MET-262; THR-278; SER-307 AND PRO-355;

Homocystinuria in the Arab population of Israel: identification of two novel mutations using DGGE analysis.
Gat-Yablonski G.; Mandel H.; Fowler B.; Taleb O.; Sela B.-A.;
Hum. Mutat. 16:372-372(2000)
Cited for: VARIANTS CBSD ARG-262 AND THR-278; VARIANT GLN-102;

Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria.
Janosik M.; Oliveriusova J.; Janosikova B.; Sokolova J.; Kraus E.; Kraus J.P.; Kozich V.;
Am. J. Hum. Genet. 68:1506-1513(2001)
Cited for: VARIANTS CBSD ARG-65; VAL-114; LYS-144; THR-155; TYR-165; LYS-176 AND THR-278; CHARACTERIZATION OF VARIANTS CBSD VAL-114; LYS-144; THR-155; TYR-165; LYS-176 AND THR-278;

High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.
Maclean K.N.; Gaustadnes M.; Oliveriusova J.; Janosik M.; Kraus E.; Kozich V.; Kery V.; Skovby F.; Ruediger N.; Ingerslev J.; Stabler S.P.; Allen R.H.; Kraus J.P.;
Hum. Mutat. 19:641-655(2002)
Cited for: VARIANTS CBSD ARG-85; THR-278; LEU-422; THR-435; ASN-444 AND LEU-466; CHARACTERIZATION OF VARIANTS CBSD ARG-85; LEU-422; THR-435 AND LEU-466;

The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.
Gaustadnes M.; Wilcken B.; Oliveriusova J.; McGill J.; Fletcher J.; Kraus J.P.; Wilcken D.E.;
Hum. Mutat. 20:117-126(2002)
Cited for: VARIANTS CBSD LEU-49; PRO-101; ARG-109; GLN-125; LYS-144; TYR-165; LYS-228; THR-278; LYS-302; SER-307; GLU-331; CYS-336; SER-347; MET-353; CYS-369; MET-371 AND GLN-439; CHARACTERIZATION OF VARIANTS CBSD PRO-101; ARG-109; LYS-228 AND SER-347;

Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype.
Kruger W.D.; Wang L.; Jhee K.H.; Singh R.H.; Elsas L.J. II;
Hum. Mutat. 22:434-441(2003)
Cited for: VARIANTS CBSD PRO-101; THR-226; SER-228; PRO-231; THR-278; SER-307; ALA-320; MET-353; ASN-376 AND LYS-526; CHARACTERIZATION OF VARIANTS CBSD PRO-101; THR-226; SER-228; PRO-231; THR-278; SER-307; ALA-320; MET-353; ASN-376 AND LYS-526;

Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria.
Orendac M.; Pronicka E.; Kubalska J.; Janosik M.; Sokolova J.; Linnebank M.; Koch H.G.; Kozich V.;
Hum. Mutat. 23:631-631(2004)
Cited for: VARIANTS CBSD MET-143; ARG-148; LYS-228 AND THR-278; CHARACTERIZATION OF VARIANTS CBSD MET-143 AND ARG-148;

Molecular analysis of homocystinuria in Brazilian patients.
Porto M.P.R.; Galdieri L.C.; Pereira V.G.; Vergani N.; da Rocha J.C.C.; Micheletti C.; Martins A.M.; Perez A.B.A.; Almeida V.D.;
Clin. Chim. Acta 362:71-78(2005)
Cited for: VARIANTS CBSD ALA-168; MET-191 AND THR-278;

CBS gene mutations found in a Chinese pyridoxine-responsive homocystinuria patient.
Kwok J.S.; Fung S.L.; Lui G.C.; Law E.L.; Chan M.H.; Leung C.B.; Tang N.L.;
Pathology 43:81-83(2011)
Cited for: VARIANTS CBSD THR-278 AND CYS-336;

Reduced response of Cystathionine Beta-Synthase (CBS) to S-Adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients.
Mendes M.I.; Colaco H.G.; Smith D.E.; Ramos R.J.; Pop A.; van Dooren S.J.; Tavares de Almeida I.; Kluijtmans L.A.; Janssen M.C.; Rivera I.; Salomons G.S.; Leandro P.; Blom H.J.;
J. Inherit. Metab. Dis. 37:245-254(2014)
Cited for: VARIANTS CBSD LEU-49; LYS-269 DEL; THR-278; HIS-336; LEU-427; ASN-444; LEU-500 AND GLN-540; CHARACTERIZATION OF VARIANTS CBSD LEU-49; LYS-269 DEL; THR-278; HIS-336; LEU-427; ASN-444; LEU-500 AND GLN-540; FUNCTION; CATALYTIC ACTIVITY; PATHWAY; ACTIVITY REGULATION;

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.