CBS I278T - GET-Evidence

Curation:
Currentness:

CBS I278T

(CBS Ile278Thr)


Short summary

This recessive mutation causes homocystinuria in a recessive manner and is found in patients responsive to pyridoxine treatment.

Variant evidence
Computational 1

Other mutations in this gene cause the disease.

See unpublished research (below).

Functional 1

Mouse model has severely reduced CBS function

See Wang L et al. 2005 (15972722), unpublished research (below).

Case/Control 5

High OR, extremely significant ( ~220, p = 4 * 10^-15)

See Kluijtmans LA et al. 1996 (8554066), unpublished research (below).

Familial -
 
Clinical importance
Severity 4

High mortality in the absence of treatment.

See unpublished research (below).

Treatability 3

No cure, but pyrodoxine treatment seems to work for this variant.

See Shih VE et al. 1995 (7611293), unpublished research (below).

Penetrance 5

Mendelian recessive

 

Impact

High clinical importance, Likely pathogenic

(The "high clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

Used Counsyl Diagnostic Screen http://precedings.nature.com/documents/4192/version/1

Total cases/controls case+ case– control+ control– p-value odds ratio
Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency
15 15 1 221 0.0000 221.000

 

Allele frequency

  • G @ chr21:44483184: 0.3% (31/10758) in EVS
  • G @ chr21:43356252: 4.2% (5/118) in GET-Evidence
  • Frequency shown in summary reports: 0.3% (31/10758)

Publications
 

Shih VE, Fringer JM, Mandell R, Kraus JP, Berry GT, Heidenreich RA, Korson MS, Levy HL, Ramesh V. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet. 1995 Jul;57(1):34-9. PubMed PMID: 7611293; PubMed Central PMCID: PMC1801250.

This study observes the I278T mutation in 7 of 11 patients responsive to pyridoxine treatment and in 0 of 27 pyridoxine-nonresponsive patients.

Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996 Jan;58(1):35-41. PubMed PMID: 8554066; PubMed Central PMCID: PMC1914961.

In 15 Dutch patients with CBS deficiency, all presumably homozygous or compound heterozygous for CBS mutations, 50% of the alleles were I278T (called 844T->C here). In a control group of 111 subjects only one heterozygote was detected.

Cases/controls case+ case– control+ control– p-value odds ratio
Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency
15 15 1 221 0.0000 221.000

 

Tsai MY, Bignell M, Schwichtenberg K, Hanson NQ. High prevalence of a mutation in the cystathionine beta-synthase gene. Am J Hum Genet. 1996 Dec;59(6):1262-7. PubMed PMID: 8940271; PubMed Central PMCID: PMC1914870.

They report on a common 68 base insertion that appears to create an alternate splicing site that causes the I278T variant to be untranslated.

Franco RF, Elion J, Lavinha J, Krishnamoorthy R, Tavella MH, Zago MA. Heterogeneous ethnic distribution of the 844ins68 in the cystathionine beta-synthase gene. Hum Hered. 1998 Nov-Dec;48(6):338-42. PubMed PMID: 9813456.

This paper observes that a 68 base pair insertion cosegregates with I278T variants and appears to have a neutralizing affect, presumably due to an effect on splicing reported on by Tsai et al.

Wang L, Chen X, Tang B, Hua X, Klein-Szanto A, Kruger WD. Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum Mol Genet. 2005 Aug 1;14(15):2201-8. Epub 2005 Jun 22. PubMed PMID: 15972722; PubMed Central PMCID: PMC1283068.

Mice homozygous for the I278T mutation were bred; liver, kidney and colon, and liver extracts have only 2-3% of the CBS enzyme activity found in wild-type mice.

Martinez CA, Northrup H, Lin JI, Morrison AC, Fletcher JM, Tyerman GH, Au KS. Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. Am J Obstet Gynecol. 2009 Oct;201(4):394.e1-11. Epub 2009 Aug 15. PubMed PMID: 19683694; PubMed Central PMCID: PMC2790326.

 

Genomes
 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het G @ chr21:44483184

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het G @ chr21:44483184

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het G @ chr21:44483184

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het G @ chr21:44483184

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het G @ chr21:44483184

 

GS19017 - var-GS19017-1100-36-ASM
het G @ chr21:43356253

 

GS19025 - var-GS19025-1100-36-ASM
het G @ chr21:43356253

 

GS19129 - var-GS19129-1100-36-ASM
het G @ chr21:43356253

 

GS19240 - var-GS19240-1100-36-ASM
het G @ chr21:43356253

 

GS19701 - var-GS19701-1100-36-ASM
het G @ chr21:43356253

 

Other external references
 

    dbSNP
  • rs5742905
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Neural Tube Defects; Spina Bifida Cystica]
    Risk or phenotype-associated allele: T Phenotype: The T variant of rs5742905 was associated with Spina Bifida in a transmission disequilibrium test. Study size: 610 families (329 trios, 281 duos) Study population/ethnicity: Patients affected with Spina Bifida and their parents; Houston, TX; Los Angeles, CA; Toronto, ON, Canada Significance metric(s): p = 0.0156 Type of association: CO
    www.ncbi.nlm.nih.gov/pubmed/19683694
  • [Homocystinuria]
    This variant has also been identified in Celtic homocystinuria patients.
    www.ncbi.nlm.nih.gov/pubmed/7506602; PubMed ID:7611293
    PolyPhen-2
  • Score: 0.047 (benign)
    Web search results (485 hits -- see all)
  • Mutations in the regulatory domain of cystathionine {beta ...
    Intragenic suppressors of V168M and I278T mutations in human CBS. ... from yeast expressing the I278T allele of CBS had undetectable levels of activity ...
    hmg.oxfordjournals.org/cgi/content/full/10/6/635
  • CBS [PharmGKB]
    rs5742905 at chr21:43356253 in CBS. This variant has also been identified in Celtic ... CBS:Ile278Thr; CBS I278T, 11bp upstream of CBS:844ins68; rs5742905T>C ...
    www.pharmgkb.org/do/serve?objId=PA26123&objCls=Gene
  • Cbs<tm1Unc> Targeted Allele Detail MGI Mouse (MGI:1857139)
    View Cbs<tm1Unc> allele: origin, molecular description, curated phenotype details and human disease models, images, gene associations, and references.
    informatics.jax.org/searches/...?id=MGI:1857139
  • Homocystinuria Caused by Cystathionine Beta-Synthase ...
    A single biochemical test cannot distinguish heterozygotes for CBS deficiency from controls. ... The two most common CBS mutations, I278T and G307S, are found in exon ...
    ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&...
  • Expression of mutant human cystathionine beta-synthase ...
    The I278T mutation is the most common mutation found in human CBS deficient patients. ... Both the I278T and the I278T/T424N transgenes are able to entirely ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1283068
  • GENTAUR - Bioxys Hemostasys
    ampli set CBS I278T - 45 test/kit. 1331C - extraction, amplification, ... ampli set CBS 844ins68 - 45 test/kit. 1332C - extraction, amplification, gel detection ...
    genoprice.com/aspnet_client/.../Catalog_Hemostasys_408.html
  • Expression of mutant human cystathionine {beta}-synthase ...
    The I278T mutation is the most common mutation found in human CBS-deficient patients. ... Both the I278T and the I278T/T424N transgenes are able to entirely ...
    hmg.oxfordjournals.org/cgi/content/full/14/15/2201
  • The Molecular Basis of Cystathionine b-Synthase Deficiency in ...
    CBS deficiency is diverse, and four major organ systems. are predominantly involved: the ... tients homozygous for I278T, and in 12 patients with. another CBS genotype (table 2) ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • GeneTests: Reviews
    A single biochemical test cannot distinguish heterozygotes for CBS deficiency from controls. ... two most common CBS mutations, I278T and G307S, are found in exon 8. The I278T ...
    snubi.org/~shats99/rare_disease/disease_review.py?...
  • Logic Regression
    CBS( I278T. r. 14. TNFR1. r. 13. MDM2. d. 9. CBS( 68bp ins. r. 9. MMP9. d. 5. APOC3 ... CBS( I278T. r. 3. APOC3( C1100T. d. TNFR1. r. 3. Top 4 three SNP interactions ...
    www.math.ualberta.ca/~mizera/Banff/Slides/kooperberg.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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