VCV000002939.22 - ClinVar

NM_001902.6(CTH):c.200C>T (p.Thr67Ile)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001902.6(CTH):c.200C>T (p.Thr67Ile)

Variation ID: 2939 Accession: VCV000002939.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.1 1: 70415987 (GRCh38) [ NCBI UCSC ] 1: 70881670 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 3, 2024	Apr 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001902.6:c.200C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001893.2:p.Thr67Ile	missense
NM_001190463.2:c.200C>T	NP_001177392.1:p.Thr67Ile	missense
NM_153742.5:c.200C>T	NP_714964.2:p.Thr67Ile	missense
NC_000001.11:g.70415987C>T
NC_000001.10:g.70881670C>T
NG_008041.1:g.9716C>T
	P32929:p.Thr67Ile

... more HGVS ... less HGVS

Protein change

T67I

Other names

CTH, THR67ILE (rs28941785)

Canonical SPDI

NC_000001.11:70415986:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00260 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00260

1000 Genomes Project 30x 0.00297

The Genome Aggregation Database (gnomAD) 0.00693

Trans-Omics for Precision Medicine (TOPMed) 0.00708

Links

ClinGen: CA115889 UniProtKB: P32929#VAR_015450 OMIM: 607657.0003 dbSNP: rs28941785 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CTH		-	-	GRCh38 GRCh37	73	103

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystathioninuria	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Apr 4, 2024	RCV000003073.17
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000727631.12
CTH-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jun 28, 2024	RCV004758588.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 05, 2018)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000854913.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CTH Number of individuals with the variant: 4 Zygosity: Single Heterozygote Sex: mixed
Uncertain significance (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystathioninuria Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004810152.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Cystathioninuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000358891.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (5) PubMed: 20584029‚ 19428278‚ 12574942‚ 19019829‚ 18476726 Comment: The c.200C>T (p.Thr67Ile) variant has been reported in three studies in which it is found in a total of 13 cystathioninuria patients including five in … (more) The c.200C>T (p.Thr67Ile) variant has been reported in three studies in which it is found in a total of 13 cystathioninuria patients including five in a homozygous state, three in a compound heterozygous state, and a five in a heterozygous state (Wang et al. 2003; Kraus et al. 2009; EspinÃ³s et al. 2010). All individuals homozygous for the p.Thr67Ile variant showed a marked elevation of plasma cystathionine. The p.Thr67Ile variant was reported in a heterozygous state in a total of six out of 822 control alleles and is reported at a frequency of 0.01869 in the Iberian population in Spain cohort of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Functional studies by Kraus et al. (2009) and Zhu et al. (2008) demonstrated that the p.Thr67Ile variant protein has decreased catalytic activity of 13 - 29% compared to wild type. Based on the collective evidence, the p.Thr67Ile variant is classified as a pathogenic variant for cystathioninuria. (less)
Uncertain significance (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystathioninuria Affected status: no Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930307.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Geographic origin: Iran
Uncertain significance (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004699236.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: CTH: PP4:Moderate, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (Dec 01, 2010)	no assertion criteria provided Method: literature only	CYSTATHIONINURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023231.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 03, 2024	Publications: PubMed (2) PubMed: 12574942‚ 20584029 Comment on evidence: In a patient of European descent (GM01565) with cystathioninuria (219500), Wang and Hegele (2003) found homozygosity for a 356C-T transition in exon 2 of the … (more) In a patient of European descent (GM01565) with cystathioninuria (219500), Wang and Hegele (2003) found homozygosity for a 356C-T transition in exon 2 of the CTH gene, resulting in a thr67-to-ile (T67I) mutation. The same mutation was found in compound heterozygosity with a gln240-to-glu mutation (Q240E; 607657.0004) in another patient of European descent. Espinos et al. (2010) identified a homozygous T67I mutation in 3 unrelated Spanish girls with cystathioninuria. Haplotype analysis of these 3 patients and of 2 Czech patients with the mutation suggested a founder effect, and the age of the mutation was estimated at 7,336 years (262 generations old). The event may have occurred during the spread of the European population in the Neolithic era. Espinos et al. (2010) noted that the 200C-T transition, which is the most common change in the CTH gene and has been observed in the heterozygous state in 1.5% of controls in the Czech population, has been considered a polymorphism (rs28941785). (less)
Likely pathogenic (Jun 28, 2024)	no assertion criteria provided Method: clinical testing	CTH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360655.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CTH c.200C>T variant is predicted to result in the amino acid substitution p.Thr67Ile. This variant has been shown to decrease the activity of the … (more) The CTH c.200C>T variant is predicted to result in the amino acid substitution p.Thr67Ile. This variant has been shown to decrease the activity of the CTH protein substantially relative to the wild-type protein, and has previously been reported to be causative for cystathioninuria (Wang and Hegele. 2003. PubMed ID: 12574942; Zhu et al. 2008. PubMed ID: 18476726; Kraus et al. 2009. PubMed ID: 19428278; Espinós et al. 2010. PubMed ID: 20584029). It should be noted that the allele frequency of the c.200C>T variant is up to ~1% in multiple populations in gnomAD. However, cystathioninuria has been reported in patients with a wide variety of disorders, ranging from more severely affected to asymptomatic individuals; thus, this relatively high allele frequency may not be inconsistent with a causative effect on the CTH protein (e.g., Wang and Hegele. 2003, PubMed ID: 12574942; Kraus et al. 2009, PubMed ID: 19428278). This variant is interpreted as likely pathogenic. (less)

Comment:

The c.200C>T (p.Thr67Ile) variant has been reported in three studies in which it is found in a total of 13 cystathioninuria patients including five in a homozygous state, three in a compound heterozygous state, and a five in a heterozygous state (Wang et al. 2003; Kraus et al. 2009; EspinÃ³s et al. 2010). All individuals homozygous for the p.Thr67Ile variant showed a marked elevation of plasma cystathionine. The p.Thr67Ile variant was reported in a heterozygous state in a total of six out of 822 control alleles and is reported at a frequency of 0.01869 in the Iberian population in Spain cohort of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. Functional studies by Kraus et al. (2009) and Zhu et al. (2008) demonstrated that the p.Thr67Ile variant protein has decreased catalytic activity of 13 - 29% compared to wild type. Based on the collective evidence, the p.Thr67Ile variant is classified as a pathogenic variant for cystathioninuria.

Comment:

The CTH c.200C>T variant is predicted to result in the amino acid substitution p.Thr67Ile. This variant has been shown to decrease the activity of the CTH protein substantially relative to the wild-type protein, and has previously been reported to be causative for cystathioninuria (Wang and Hegele. 2003. PubMed ID: 12574942; Zhu et al. 2008. PubMed ID: 18476726; Kraus et al. 2009. PubMed ID: 19428278; Espinós et al. 2010. PubMed ID: 20584029). It should be noted that the allele frequency of the c.200C>T variant is up to ~1% in multiple populations in gnomAD. However, cystathioninuria has been reported in patients with a wide variety of disorders, ranging from more severely affected to asymptomatic individuals; thus, this relatively high allele frequency may not be inconsistent with a causative effect on the CTH protein (e.g., Wang and Hegele. 2003, PubMed ID: 12574942; Kraus et al. 2009, PubMed ID: 19428278). This variant is interpreted as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria.	Espinós C	Clinical genetics	2010	PMID: 20584029
Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.	Kraus JP	Molecular genetics and metabolism	2009	PMID: 19428278
Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S.	Sun Q	The Journal of biological chemistry	2009	PMID: 19019829
Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine gamma-lyase.	Zhu W	Biochemistry	2008	PMID: 18476726
Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH).	Wang J	Human genetics	2003	PMID: 12574942
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CTH	-	-	-	-

Text-mined citations for rs28941785 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001902.6(CTH):c.200C>T (p.Thr67Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28941785 ...