CBS

protein-coding

cystathionine beta-synthase

Gene summary

The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

MANE transcript

NM_000071.3

Inheritance

ClinVar variants

P:330U:309B:401

Top phenotype

Homocystinuria due to cystathionine beta-synthase deficiency

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr21:43,053,191-43,076,943

External References & Databases

Ensembl (ENSG00000160200)

Transcript & Mutation Effects

hg38 • Region Span ~23.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

classic homocystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: Myriad Women's Health

classic homocystinuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: Labcorp Genetics (formerly Invitae)

classic homocystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: G2P

classic homocystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: Natera

classic homocystinuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: Orphanet

classic homocystinuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: ClinGen

The relationship between CBS and classic homocysteinuria, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 26th, 2019. CBS encodes cystathione beta-synthase which catalyses the first step of the transsulfuration pathway, from homocysteine to cystathione. Variants in CBS were first reported in humans with this disorder in 1992 (Kozich and Kraus, PMID 1301198). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (Kozich and Kraus, 1992, PMID 1301198; De Franchis et al, 1999, PMID 10408774; Sebastio et al, 1999, PMID 7762555; Urreizti et al, 2003, PMID 12815602; Katsushima et al, 2006, PMID 16307898; Suri et al, 2014, PMID 25455305; Gong et al, 2015, PMID 26667307; Li et al, 2018, PMID 29508359). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (Selim et al, 1959, PMID 13654400; Jhee and Kruger, 2005, PMID 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (Shan et al, 1998, PMID 9590298; Melenovská et al, 2018, PMID 25331909), as well as the biochemical and clinical features of mouse models (Gupta et al, 2009, PMID 18987302) and enzyme replacement studies in mice (Matjan et al, 2018, PMID 29398487). More information is available but the maximum experimental evidence score (6 points) has been reached. In summary, CBS is definitively associated with classic homocystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 12, 2019.

classic homocystinuriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009352

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Homocystinuria due to cystathionine beta-synthase deficiencyAR

Manifestation: Biochemical; Cardiovascular; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical; Hematologic; Ophthalmologic; Pharmacogenomic

Rationale: 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

Refs: 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

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CBS variants in ClinVar

20 Conditions Cataloged

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATEDTotal: 1016

Classic homocystinuriaTotal: 442

Familial thoracic aortic aneurysm and aortic dissectionTotal: 361

not providedTotal: 347

not specifiedTotal: 214

CBS-related disorderTotal: 100

HomocystinuriaTotal: 75

Connective tissue disorderTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000071.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	349 clinvar	5 clinvar	363
missense	22 clinvar	118 clinvar	292 clinvar	16 clinvar	2 clinvar	450
nonsense	18 clinvar	28 clinvar	3 clinvar	3 clinvar	11 clinvar	63
start loss		2 clinvar				2
frameshift	47 clinvar	36 clinvar	2 clinvar	3 clinvar	12 clinvar	100
splice donor/acceptor (+/-2bp)	14 clinvar	45 clinvar	3 clinvar			62
Total	101	229	309	371	30	1040

Highest pathogenic variant AF is 0.0005050505

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 145 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000071.3	RefSeq	NP_000062.1	15	MANE Select
ENST00000398165.8	Ensembl	ENSP00000381231.4	15	MANE Select
NM_001178008.3	RefSeq	NP_001171479.1	15	Standard
NM_001178009.3	RefSeq	NP_001171480.1	15	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cbsb	Danio rerio	Structure: trunk Quality: bent abnormal

Gene / Model

Organism

Observed Phenotype

cbsb

Danio rerio

Structure: trunk

Quality: bent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

cysteine biosynthetic process from serine
L-serine metabolic process
L-serine catabolic process
cysteine biosynthetic process via cystathionine
cysteine biosynthetic process

Molecular Function

cystathionine beta-synthase activity
cysteine synthase activity
protein binding
oxygen binding
enzyme binding

Cellular Component

nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398165
Coding exons: 15
Length: 23753
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125747
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.832	301	344	0.874	0.0000251	3538
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.0014	0.0013	notable
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.848

Intolerance Scores

LoFtool: 0.0305
RVIS EVS: -0.8
RVIS percentile EVS: 12.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.984

Gene Damage Prediction

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