CBS

Chr 21AR

cystathionine beta-synthase

Also known as: HIP4

NCBI Gene: 875 ENSG00000160200 UniProt: P35520 OMIM: 613381

The encoded protein functions as a homotetramer that catalyzes the conversion of homocysteine to cystathionine in the transsulfuration pathway, using pyridoxal phosphate as a cofactor and activated by adenosyl-methionine. Mutations cause autosomal recessive cystathionine beta-synthase deficiency leading to homocystinuria (both B6-responsive and nonresponsive types) and hyperhomocysteinemic thrombosis. The pathogenic mechanism involves loss of enzymatic function resulting in toxic accumulation of homocysteine.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Homocystinuria, B6-responsive and nonresponsive typesMIM #236200

Thrombosis, hyperhomocysteinemicMIM #236200

UniProtCystathionine beta-synthase deficiency

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · classic homocystinuria · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1221

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.73

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CBS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.000

Z-score 2.64

OE 0.45 (0.29–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.87 (0.79–0.96)

301 obs / 344.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.29–0.73)

0≤0.351.4

Missense OE?0.87 (0.79–0.96)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 12 / 26.7Missense obs/exp: 301 / 344.4Syn Z: -1.11

Background carrier burden — how many people carry a rare variant somewhere in CBS?

gnomAD v4 · ~646k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

43 rare PASS variants

Rare truncating (LoF)

1 in 280

14 rare PASS variants

Rare synonymous (reference)

1 in 290

30 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CBS; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 7 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~483k	1 in 270	1 in 480
South Asian	~40k	1 in 250	1 in 1,100
Remaining (unassigned)	~27k	1 in 310	1 in 510
European (Finnish)	~25k	1 in 540	1 in 1,100
Admixed American	~21k	1 in 260	1 in 320
East Asian	~20k	1 in 200	none seen
African / African American	~18k	1 in 180	1 in 1,300

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 0 of 15 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 6, 7 and 9 more poorly covered; exon 8 marginal. Genomes: 0 of 15 (exons 3, 4, 5, 6, 7 and 10 more below).? see exons ↓