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NM_000071.2(CBS):c.833T>C (p.Ile278Thr)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
13 (Most recent: May 8, 2019)
Last evaluated:
Jan 24, 2019
Accession:
VCV000000120.6
Variation ID:
120
Description:
single nucleotide variant
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NM_000071.2(CBS):c.833T>C (p.Ile278Thr)

Allele ID
15159
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
21q22.3
Genomic location
21: 43063074 (GRCh38) GRCh38 UCSC
21: 44483184 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000021.9:g.43063074A>G
NC_000021.8:g.44483184A>G
NM_000071.2:c.833T>C NP_000062.1:p.Ile278Thr missense
... more HGVS
Protein change
I278T
Other names
p.I278T:ATT>ACT
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (G)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00083
1000 Genomes Project 0.00020
Links
UniProtKB: P35520#VAR_002184
OMIM: 613381.0004
dbSNP: rs5742905
ClinGen: CA113880
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 3 criteria provided, multiple submitters, no conflicts Aug 14, 2018 RCV000078111.10
Pathogenic 5 criteria provided, multiple submitters, no conflicts Jan 24, 2019 RCV000173640.13
Pathogenic 1 criteria provided, single submitter Jan 15, 2018 RCV000249462.3
Pathogenic 1 criteria provided, single submitter Aug 15, 2016 RCV000507410.1
Pathogenic 1 criteria provided, single submitter Jan 22, 2018 RCV000781197.1
Pathogenic 1 no assertion criteria provided Jan 1, 2010 RCV000000141.6
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Pathogenic 1 no assertion criteria provided Jan 1, 2010 RCV000000142.6
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CBS - - GRCh38
GRCh37
435 509

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 15, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602918.1
Submitted: (Jun 30, 2017)
Evidence details
Pathogenic
(Oct 27, 2015)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to CBS deficiency
Allele origin: unknown
Counsyl
Accession: SCV000678073.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (7)
Comment:
The I278T mutation is associated with the B6-responsive form of this disease.
Pathogenic
(Jan 15, 2018)
criteria provided, single submitter
Method: clinical testing
cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000319225.4
Submitted: (Jul 30, 2018)
Evidence details
Publications
PubMed (5)
Comment:
Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation ... (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to CBS deficiency
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893555.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Aug 14, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000249694.14
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The pathogenic I278T variant in the CBS gene has been identified in nearly 25% of all CBS alleles from patients of varied ethnic backgrounds with ... (more)
Pathogenic
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to CBS deficiency
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000436218.3
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (8)
Comment:
The CBS c.833T>C (p.Ile278Thr) variant is the most common variant associated with homocystinuria, overall accounting for 25% of all pathogenic variants, including 29% of the ... (more)
Pathogenic
(Jan 22, 2018)
criteria provided, single submitter
Method: clinical testing
Homocystinuria
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000919082.1
Submitted: (Apr 24, 2019)
Evidence details
Publications
PubMed (9)
Comment:
Variant summary: The CBS c.833T>C (p.Ile278Thr) variant involves the alteration of a conserved nucleotide that is located in the Pyridoxal-phosphate dependent enzyme domain (InterPro). 4/4 ... (more)
Pathogenic
(Feb 08, 2018)
criteria provided, single submitter
Method: clinical testing
Not provided
Allele origin: germline
Blueprint Genetics
Accession: SCV000927527.1
Submitted: (May 08, 2019)
Comment:
Patient analyzed with Aorta Panel
Evidence details
Pathogenic
(Nov 20, 2014)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000224772.5
Submitted: (Jun 30, 2017)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(Jan 02, 2019)
criteria provided, single submitter
Method: clinical testing
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Allele origin: germline
Invitae
Accession: SCV000283389.6
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (19)
Comment:
This sequence change replaces isoleucine with threonine at codon 278 of the CBS protein (p.Ile278Thr). The isoleucine residue is moderately conserved and there is a ... (more)
Pathogenic
(Jan 24, 2019)
criteria provided, single submitter
Method: clinical testing
Homocystinuria due to CBS deficiency
(Autosomal recessive inheritance)
Allele origin: germline
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000245588.2
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (4)
Comment:
The p.Ile278Thr variant in CBS is one of the most commonly observed pathogenic v ariants in patients with homocystinuria (Moat 2004, Skovby 2010), has been ... (more)
Pathogenic
(Jan 01, 2010)
no assertion criteria provided
Method: literature only
HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE
Allele origin: germline
OMIM
Accession: SCV000020284.5
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (10)
Pathogenic
(Jan 01, 2010)
no assertion criteria provided
Method: literature only
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Allele origin: germline
OMIM
Accession: SCV000020285.5
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (10)

Citations for this variant

Title Author Journal Year Link
Homocystinuria due to cystathionine beta-synthase (CBS) deficiency in Russia: Molecular and clinical characterization. Voskoboeva E Molecular genetics and metabolism reports 2017 PMID: 29326875
Cystathionine β-synthase deficiency: Of mice and men. Kruger WD Molecular genetics and metabolism 2017 PMID: 28583326
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Sørensen JT Molecular genetics and metabolism 2016 PMID: 26750749
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis. Awan Z Thrombosis journal 2014 PMID: 25516723
Correction of cystathionine β-synthase deficiency in mice by treatment with proteasome inhibitors. Gupta S Human mutation 2013 PMID: 23592311
Surrogate genetics and metabolic profiling for characterization of human disease alleles. Mayfield JA Genetics 2012 PMID: 22267502
Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. Hnízda A Journal of inherited metabolic disease 2012 PMID: 22069143
Vascular presentation of cystathionine beta-synthase deficiency in adulthood. Magner M Journal of inherited metabolic disease 2011 PMID: 20567906
Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. Kozich V Human mutation 2010 PMID: 20506325
A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Skovby F Molecular genetics and metabolism 2010 PMID: 19819175
[Stroke and iridodonesis revealing a homocystinuria caused by a compound heterozygous mutation of cystathionine beta-synthase]. Lefaucheur R Revue neurologique 2008 PMID: 18805305
Origin and evolution of the c.844_845ins68/c.833T>C mutations within the cystathionine beta-synthase gene in great apes. Romano M FEBS letters 2008 PMID: 18201569
Chemical chaperone rescue of mutant human cystathionine beta-synthase. Singh LR Molecular genetics and metabolism 2007 PMID: 17540596
Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Vyletal P Human mutation 2007 PMID: 17072863
Cystathionine beta-synthase T833C/844INS68 polymorphism: a family-based study on mentally retarded children. Dutta S Behavioral and brain functions : BBF 2005 PMID: 16375773
Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria. Orendáè M Human mutation 2004 PMID: 15146473
The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Moat SJ Human mutation 2004 PMID: 14722927
Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Kelly PJ Neurology 2003 PMID: 12552044
High prevalence of the I278T mutation of the human cystathionine beta-synthase detected by a novel screening application. Linnebank M Thrombosis and haemostasis 2001 PMID: 11434706
Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Janosík M American journal of human genetics 2001 PMID: 11359213
Mutations in the regulatory domain of cystathionine beta synthase can functionally suppress patient-derived mutations in cis. Shan X Human molecular genetics 2001 PMID: 11230183
Familial thrombophilia associated with homozygosity for the cystathionine beta-synthase 833T-->C mutation. Gaustadnes M Arteriosclerosis, thrombosis, and vascular biology 2000 PMID: 10807759
The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Kluijtmans LA American journal of human genetics 1999 PMID: 10364517
Cystathionine beta-synthase mutations in homocystinuria. Kraus JP Human mutation 1999 PMID: 10338090
Prevalence of congenital homocystinuria in Denmark. Gaustadnes M The New England journal of medicine 1999 PMID: 10328723
The frequency of 844ins68 mutation in the cystathionine beta-synthase gene is not increased in patients with venous thrombosis. Franco R Haematologica 1998 PMID: 9864922
Detection of a novel deletion in the cystathionine beta-synthase (CBS) gene using an improved genomic DNA based method. Gaustadnes M FEBS letters 1998 PMID: 9708897
High prevalence of a mutation in the cystathionine beta-synthase gene. Tsai MY American journal of human genetics 1996 PMID: 8940271
Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations. Sperandeo MP Journal of inherited metabolic disease 1996 PMID: 8803779
Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Kluijtmans LA American journal of human genetics 1996 PMID: 8554066
The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. Sebastio G American journal of human genetics 1995 PMID: 7762555
Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients. Kluijtmans LA Human genetics 1995 PMID: 7635485
A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Shih VE American journal of human genetics 1995 PMID: 7611293
Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hu FL Human molecular genetics 1993 PMID: 7506602
Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency. Kozich V Human mutation 1992 PMID: 1301198
[Hospital outbreak of salmonellosis with secondary cases]. Bellido Blasco J Medicina clinica 1991 PMID: 2056790
Homocystinuria: biogenesis of cystathionine beta-synthase subunits in cultured fibroblasts and in an in vitro translation system programmed with fibroblast messenger RNA. Skovby F American journal of human genetics 1984 PMID: 6711564
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS - - - -

Record last updated Oct 27, 2019