CBS

cystathionine beta-synthase

Basic information

Region (hg38): 21:43053191-43076943

Links

ENSG00000160200 ∙ NCBI:875 ∙ OMIM:613381 ∙ HGNC:1550 ∙ Uniprot:P35520 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• classic homocystinuria (Definitive), mode of inheritance: AR
• classic homocystinuria (Definitive), mode of inheritance: AR
• classic homocystinuria (Strong), mode of inheritance: AR
• classic homocystinuria (Strong), mode of inheritance: AR
• classic homocystinuria (Strong), mode of inheritance: AR
• classic homocystinuria (Supportive), mode of inheritance: AR
• classic homocystinuria (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Homocystinuria due to cystathionine beta-synthase deficiency	AR	Biochemical; Hematologic; Ophthalmologic; Pharmacogenomic	Some individuals may respond to medical therapy (eg, pyridoxine, folic acid, betaine, hydroxycobalamin) and/or dietary therapy (eg, methionine restriction); Surveillance for and prompt treatment of thromboembolic complications can be beneficial; Awareness of ocular complications (eg, ectopia lentis) can allow prompt and appropriate treatment; Certain agents (eg, oral contraceptives) should be avoided, and special considerations may need to be taken into account if surgery is required	Biochemical; Cardiovascular; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	14018926; 13960563; 5658872; 5658866; 7325153; 6711564; 4033699; 934499; 3591841; 2116556; 7506602; 7967489; 7762555; 8554066; 8592550; 8940271; 9427154; 9787359; 10364517; 10338090; 10564686; 10780316; 11343305; 11596648; 12124992; 12227460; 12007221; 12118525; 11857551; 12552044; 14635102; 16205833; 17686644; 20142522; 20301697; 18280597; 19370759; 19819175; 21520339; 21308989; 21240075; 20567906; 21626167; 24168815; 24169224

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CBS gene.

• HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (59 variants)
• Classic homocystinuria (26 variants)
• Homocystinuria (15 variants)
• not provided (15 variants)
• Familial thoracic aortic aneurysm and aortic dissection (5 variants)
• CBS-related disorder (4 variants)
• Homocystinuria, pyridoxine-responsive (2 variants)
• See cases (2 variants)
• Connective tissue disorder (1 variants)
• Intellectual disability (1 variants)
• Homocystinuria, pyridoxine-nonresponsive (1 variants)
• Thoracic aortic aneurysm or dissection (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CBS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	282	3	286
missense	21	85	223	4		333
nonsense	14	21	1	2	14	52
start loss						0
frameshift	24	34			1	59
inframe indel	1	1	6			8
splice donor/acceptor (+/-2bp)	9	44	2			55
splice region		2	20	66		88
non coding			25	204	53	282
Total	69	185	258	492	71

Highest pathogenic variant AF is 0.0000860

Variants in CBS

This is a list of pathogenic ClinVar variants found in the CBS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
21-43053199-T-C		Classic homocystinuria	Benign/Likely benign (May 25, 2021)
21-43053288-A-T		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053314-C-T		Classic homocystinuria	Benign/Likely benign (Sep 03, 2021)
21-43053315-G-A		Classic homocystinuria	Benign (May 10, 2021)
21-43053336-A-G		Classic homocystinuria	Benign (May 10, 2021)
21-43053340-C-T		Classic homocystinuria • not specified • HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	Conflicting classifications of pathogenicity (Dec 06, 2023)
21-43053408-G-A		Classic homocystinuria	Uncertain significance (Jan 12, 2018)
21-43053471-C-A		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053471-C-T		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053486-G-A		Classic homocystinuria	Uncertain significance (Apr 06, 2018)
21-43053497-G-A		Classic homocystinuria	Benign/Likely benign (May 11, 2021)
21-43053575-A-G		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053581-C-T		Classic homocystinuria	Benign (Jun 14, 2018)
21-43053584-A-G		Classic homocystinuria	Uncertain significance (Apr 28, 2017)
21-43053594-T-C		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053740-C-T		Classic homocystinuria	Uncertain significance (Jan 13, 2018)
21-43053748-C-G		Classic homocystinuria	Uncertain significance (Jan 12, 2018)
21-43053757-G-C		Classic homocystinuria	Benign (Jan 13, 2018)
21-43053772-TGCCAG-T		Homocystinuria	Benign (Jun 14, 2016)
21-43053799-C-T		Classic homocystinuria	Benign/Likely benign (Jul 31, 2018)
21-43053800-G-A		Classic homocystinuria	Uncertain significance (Jan 12, 2018)
21-43053822-CGAA-C		Homocystinuria	Uncertain significance (Jun 14, 2016)
21-43053824-AAGG-A			Likely benign (Mar 17, 2021)
21-43053846-C-T		not specified • Classic homocystinuria	Benign/Likely benign (Jan 13, 2018)
21-43053852-C-T		not specified	Uncertain significance (Jan 12, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CBS	protein_coding	protein_coding	ENST00000398165	15	23753

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000308	0.997	125695	0	52	125747	0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.832	301	344	0.874	0.0000251	3538
Missense in Polyphen		80	114.24	0.70027		1191
Synonymous	-1.11	176	158	1.11	0.0000136	1091
Loss of Function	2.64	12	26.7	0.450	0.00000127	314

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000246	0.000241
Ashkenazi Jewish	0.00139	0.00129
East Asian	0.000224	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.000202	0.000193
Middle Eastern	0.000224	0.000217
South Asian	0.000229	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Hydro-lyase catalyzing the first step of the transsulfuration pathway, where the hydroxyl group of L-serine is displaced by L-homocysteine in a beta-replacement reaction to form L-cystathionine, the precursor of L-cysteine. This catabolic route allows the elimination of L-methionine and the toxic metabolite L- homocysteine (PubMed:23981774, PubMed:20506325, PubMed:23974653). Also involved in the production of hydrogen sulfide, a gasotransmitter with signaling and cytoprotective effects on neurons (By similarity). {ECO:0000250|UniProtKB:P32232, ECO:0000269|PubMed:20506325, ECO:0000269|PubMed:23974653, ECO:0000269|PubMed:23981774}.
• Pathway: Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;Cysteine and methionine metabolism - Homo sapiens (human);Glycine, serine and threonine metabolism - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;3-Phosphoglycerate dehydrogenase deficiency;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Non Ketotic Hyperglycinemia;Glycine and Serine Metabolism;Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Selenoamino Acid Metabolism;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Homocysteine Degradation;Gamma-cystathionase deficiency (CTH);Homocystinuria, cystathionine beta-synthase deficiency;Cystathionine Beta-Synthase Deficiency;Dihydropyrimidine Dehydrogenase Deficiency (DHPD);Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate-Alcohol and Cancer Pathway Hypotheses;Folate Metabolism;Trans-sulfuration pathway;Trans-sulfuration and one carbon metabolism;Vitamin D Receptor Pathway;Amino Acid metabolism;Metabolism of amino acids and derivatives;Glycine Serine metabolism;Metabolism;Methionine Cysteine metabolism;Selenoamino acid metabolism;Cysteine formation from homocysteine;Metabolism of ingested SeMet, Sec, MeSec into H2Se;Methionine and cysteine metabolism;Selenoamino acid metabolism;Putative anti-Inflammatory metabolites formation from EPA;hydrogen sulfide biosynthesis (trans-sulfuration);cysteine biosynthesis/homocysteine degradation (trans-sulfuration);Sulfur amino acid metabolism;cysteine biosynthesis;superpathway of methionine degradation (Consensus)

Recessive Scores

• pRec: 0.848

Intolerance Scores

• loftool: 0.0305
• rvis_EVS: -0.8
• rvis_percentile_EVS: 12.53

Haploinsufficiency Scores

• pHI: 0.532
• hipred: Y
• hipred_score: 0.694
• ghis: 0.549

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.984

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cbs
• Phenotype: muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; embryo phenotype; respiratory system phenotype; liver/biliary system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: cbsb
• Affected structure: trunk
• Phenotype tag: abnormal
• Phenotype quality: bent

Gene ontology

• Biological process: cysteine biosynthetic process from serine;L-serine metabolic process;L-serine catabolic process;cysteine biosynthetic process via cystathionine;cysteine biosynthetic process;transsulfuration;L-cysteine catabolic process;DNA protection;homocysteine catabolic process;homocysteine metabolic process;oxidation-reduction process;hydrogen sulfide biosynthetic process
• Cellular component: nucleus;cytoplasm;cytosol
• Molecular function: cystathionine beta-synthase activity;cysteine synthase activity;protein binding;oxygen binding;enzyme binding;heme binding;pyridoxal phosphate binding;ubiquitin protein ligase binding;identical protein binding;protein homodimerization activity;metal ion binding;nitrite reductase (NO-forming) activity;carbon monoxide binding;nitric oxide binding;modified amino acid binding;S-adenosyl-L-methionine binding