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

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Apr 4, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003073.17

Allele description [Variation Report for NM_001902.6(CTH):c.200C>T (p.Thr67Ile)]

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

Gene:

CTH:cystathionine gamma-lyase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.1

Genomic location:

Preferred name:

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

Other names:

CTH, THR67ILE (rs28941785)

HGVS:

NC_000001.11:g.70415987C>T
NG_008041.1:g.9716C>T
NM_001190463.2:c.200C>T
NM_001902.6:c.200C>TMANE SELECT
NM_153742.5:c.200C>T
NP_001177392.1:p.Thr67Ile
NP_001893.2:p.Thr67Ile
NP_714964.2:p.Thr67Ile
NC_000001.10:g.70881670C>T
NM_001902.5:c.200C>T
P32929:p.Thr67Ile

Protein change:

T67I; THR67ILE

Links:

UniProtKB: P32929#VAR_015450; OMIM: 607657.0003; dbSNP: rs28941785

NCBI 1000 Genomes Browser:

rs28941785

Molecular consequence:

NM_001190463.2:c.200C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001902.6:c.200C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153742.5:c.200C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystathioninuria
Synonyms:: CYSTATHIONASE DEFICIENCY; Gamma-cystathionase deficiency
Identifiers:: MONDO: MONDO:0009058; MedGen: C0220993; Orphanet: 212; OMIM: 219500; Human Phenotype Ontology: HP:0003153

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023231	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12574942, 20584029
SCV000358891	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20584029, 19428278, 12574942, 19019829, 18476726 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000930307	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 27, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004810152	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria.

Espinós C, García-Cazorla A, Martínez-Rubio D, Martínez-Martínez E, Vilaseca MA, Pérez-Dueñas B, Kožich V, Palau F, Artuch R.

Clin Genet. 2010 Dec;78(6):554-9. doi: 10.1111/j.1399-0004.2010.01431.x.

PubMed [citation]

PMID:: 20584029

Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.

Kraus JP, Hasek J, Kozich V, Collard R, Venezia S, Janosíková B, Wang J, Stabler SP, Allen RH, Jakobs C, Finn CT, Chien YH, Hwu WL, Hegele RA, Mudd SH.

Mol Genet Metab. 2009 Aug;97(4):250-9. doi: 10.1016/j.ymgme.2009.04.001. Epub 2009 Apr 9.

PubMed [citation]

PMID:: 19428278
PMCID:: PMC2752209

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000023231.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000358891.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000930307.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004810152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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