CTH

cystathionine gamma-lyase

Basic information

Region (hg38): 1:70411218-70439851

Links

ENSG00000116761 ∙ NCBI:1491 ∙ OMIM:607657 ∙ HGNC:2501 ∙ Uniprot:P32929 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cystathioninuria (Moderate), mode of inheritance: AR
• cystathioninuria (Supportive), mode of inheritance: AR
• cystathioninuria (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cystathioninuria	AR	General	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	Biochemical	14399948; 5637757; 12574942; 20584029
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

ClinVar

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

• Cystathioninuria (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CTH 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			2	1		3
missense			22	2		24
nonsense		1	1			2
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			1			1
non coding			24	5	3	32
Total	1	1	51	8	3

Highest pathogenic variant AF is 0.0000789

Variants in CTH

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

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

Position	Type	Phenotype	Significance	ClinVar
1-70411265-T-C		Cystathioninuria	Uncertain significance (Jan 12, 2018)
1-70411276-A-T		Cystathioninuria	Likely benign (Jan 13, 2018)
1-70411413-A-G		Cystathioninuria	Uncertain significance (Jan 12, 2018)
1-70411430-C-A		Cystathioninuria • Inborn genetic diseases	Uncertain significance (Apr 11, 2023)
1-70411452-C-A		Inborn genetic diseases	Uncertain significance (May 18, 2022)
1-70411543-T-C		Inborn genetic diseases	Uncertain significance (Mar 06, 2023)
1-70411544-G-A		Cystathioninuria	Likely benign (Jan 13, 2018)
1-70411553-G-A		CTH-related disorder	Likely benign (Sep 25, 2019)
1-70415987-C-T		Cystathioninuria • CTH-related disorder	Conflicting classifications of pathogenicity (Apr 04, 2024)
1-70417955-G-C		Inborn genetic diseases	Uncertain significance (Aug 12, 2021)
1-70417975-A-G		Inborn genetic diseases	Uncertain significance (Dec 02, 2022)
1-70417997-G-A		Inborn genetic diseases	Uncertain significance (Jul 08, 2022)
1-70418039-G-A		Cystathioninuria • CTH-related disorder	Conflicting classifications of pathogenicity (Jan 30, 2018)
1-70421600-A-G		Cystathioninuria	Uncertain significance (Jan 12, 2018)
1-70421600-A-T		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
1-70421649-G-C		Cystathioninuria	Uncertain significance (Jan 13, 2018)
1-70424293-G-A		Cystathioninuria	Uncertain significance (Dec 10, 2018)
1-70424301-C-T		Inborn genetic diseases	Uncertain significance (May 26, 2023)
1-70424323-G-T		Cystathioninuria	Uncertain significance (Jan 13, 2018)
1-70424328-T-C		Inborn genetic diseases	Likely benign (May 04, 2023)
1-70424369-G-A		Inborn genetic diseases • Cystathioninuria	Uncertain significance (May 17, 2023)
1-70429791-C-T		Cystathioninuria	Uncertain significance (Jan 12, 2018)
1-70430302-G-C		Cystathioninuria	Uncertain significance (Jan 12, 2018)
1-70430343-G-A		Inborn genetic diseases	Uncertain significance (Sep 23, 2023)
1-70430355-T-C		Cystathioninuria	Uncertain significance (Apr 27, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CTH	protein_coding	protein_coding	ENST00000370938	12	28634

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.48e-8	0.901	125676	0	71	125747	0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.412	204	221	0.922	0.0000109	2652
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000145	0.000145
Ashkenazi Jewish	0.00	0.00
East Asian	0.000490	0.000489
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000352	0.000352
Middle Eastern	0.000490	0.000489
South Asian	0.000392	0.000392
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: 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;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;Cysteine Metabolism;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Selenoamino Acid Metabolism;Cystinosis, ocular nonnephropathic;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 Metabolism;Trans-sulfuration pathway;Trans-sulfuration and one carbon metabolism;Amino Acid metabolism;One carbon metabolism and related pathways;Degradation of cysteine and homocysteine;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;hydrogen sulfide biosynthesis (trans-sulfuration);cysteine biosynthesis/homocysteine degradation (trans-sulfuration);Sulfur amino acid metabolism;cysteine biosynthesis;superpathway of methionine degradation (Consensus)

Intolerance Scores

• loftool: 0.203
• rvis_EVS: 0.19
• rvis_percentile_EVS: 67.03

Haploinsufficiency Scores

• pHI: 0.246
• hipred: N
• hipred_score: 0.250
• ghis: 0.423

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.962

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cth
• Phenotype: vision/eye phenotype; renal/urinary system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); 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); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• 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;transsulfuration;endoplasmic reticulum unfolded protein response;positive regulation of I-kappaB kinase/NF-kappaB signaling;protein sulfhydration;positive regulation of NF-kappaB transcription factor activity;protein homotetramerization;hydrogen sulfide biosynthetic process;positive regulation of aortic smooth muscle cell differentiation;cellular response to leukemia inhibitory factor;negative regulation of apoptotic signaling pathway
• Cellular component: cytoplasm;cytosol;extracellular exosome
• Molecular function: cystathionine gamma-lyase activity;protein binding;calmodulin binding;carbon-sulfur lyase activity;pyridoxal phosphate binding;identical protein binding;L-cystine L-cysteine-lyase (deaminating);homocysteine desulfhydrase activity;L-cysteine desulfhydrase activity