CTH

protein-coding

cystathionine gamma-lyase

Gene summary

This gene encodes a cytoplasmic enzyme in the trans-sulfuration pathway that converts cystathione derived from methionine into cysteine. Glutathione synthesis in the liver is dependent upon the availability of cysteine. Mutations in this gene cause cystathioninuria. Alternative splicing of this gene results in three transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

MANE transcript

NM_001902.6

Inheritance

ClinVar variants

P:5U:60B:6

Top phenotype

Cystathioninuria

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr1:70,411,218-70,439,851

External References & Databases

Ensembl (ENSG00000116761)

Transcript & Mutation Effects

hg38 • Region Span ~28.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cystathioninuriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009058

Submitter: Ambry Genetics

cystathioninuriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009058

Submitter: ClinGen

The relationship between CTH and Cystathioninuria (Autosomal Recessive) was evaluated using the ClinGen Clinical Validity Framework as of 04/17/19. Variants in CTH were first reported in humans with this disease as early as 2003 (Wang et al, PMID: 12574942). At least 6 unique variants and one large deletion have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 11 probands in 3 publications (PMIDs: 20584029, 19428278, 12574942). This gene-disease association is supported by a mouse model of Cystathioninuria. The biochemical function of cystathionine gamma-lyase, which is the enzyme responsible for catalyzing the cystathionine to cysteine reaction, is also supportive of a role in the disease. In summary, CTH is definitively associated with Cystathioninuria (Autosomal Recessive). This has been repeatedly demonstrated in both the functional research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 6/14/19 (SOP Version 6).

cystathioninuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009058

Submitter: Orphanet

Clinical Genomic Database (CGD)

CystathioninuriaAR

Manifestation: Biochemical

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: It is unclear if the condition causes clinical manifestations other than biochemical abnormalities, and medical management (eg, with pyridoxine) may improve the biochemical parameters, though it is unclear if possibly coincident clinical findings are also affected

Refs: 14399948; 5637757; 12574942; 20584029

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTH variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 48

CystathioninuriaTotal: 25

not providedTotal: 8

not specifiedTotal: 6

CTH-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001902.6. 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			2 clinvar	4 clinvar		6
missense	1 clinvar	1 clinvar	56 clinvar	2 clinvar		60
nonsense		1 clinvar				1
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	3	60	6	0	71

Highest pathogenic variant AF is 0.008026102

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001902.6	RefSeq	NP_001893.2	12	MANE Select
ENST00000370938.8	Ensembl	ENSP00000359976.3	12	MANE Select
NM_001190463.2	RefSeq	NP_001177392.1	11	Standard
NM_153742.5	RefSeq	NP_714964.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cysteine and methionine metabolism - Homo sapiens (human)
Selenocompound metabolism - Homo sapiens (human)
Glycine, serine and threonine metabolism - Homo sapiens (human)
Busulfan Pathway, Pharmacodynamics
Beta-mercaptolactate-cysteine disulfiduria

Biological Process

sulfur amino acid catabolic process
cysteine metabolic process
protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine
cysteine biosynthetic process via cystathionine
cysteine biosynthetic process

Molecular Function

cystathionine gamma-lyase activity
protein binding
calmodulin binding
carbon-sulfur lyase activity
pyridoxal phosphate binding

Cellular Component

cytoplasm
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370938
Coding exons: 12
Length: 28634
Individuals with no LoFs: 125676
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125747
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.412	204	221	0.922	0.0000109	2652
Missense (PolyPhen)		82	100.46	0.81621		1116
Synonymous	0.160	75	76.8	0.977	0.00000376	779
Loss of Function	1.72	15	24.1	0.623	0.00000134	266

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00039	0.00039	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the last step in the trans-sulfuration pathway from methionine to cysteine. Has broad substrate specificity. Converts cystathionine to cysteine, ammonia and 2-oxobutanoate. Converts two cysteine molecules to lanthionine and hydrogen sulfide. Can also accept homocysteine as substrate. Specificity depends on the levels of the endogenous substrates. Generates the endogenous signaling molecule hydrogen sulfide (H2S), and so contributes to the regulation of blood pressure. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function. {ECO:0000269|PubMed:19019829, ECO:0000269|PubMed:19261609, ECO:0000269|PubMed:22169477}.;
Disease: DISEASE: Cystathioninuria (CSTNU) [MIM:219500]: Autosomal recessive phenotype characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. {ECO:0000269|PubMed:12574942, ECO:0000269|PubMed:18476726}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.203
RVIS EVS: 0.19
RVIS percentile EVS: 67.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

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