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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:
RCV000003073.14

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000023231OMIM
no assertion criteria provided
Pathogenic
(Dec 1, 2010)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000358891Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification 20161018)
Pathogenic
(Jun 14, 2016)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000930307Genomic Research Center, Shahid Beheshti University of Medical Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 27, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004810152Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 4, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownnonot providednot providednot providednot providednot providedclinical 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, SCV000023231.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a patient of European descent with cystathioninuria (219500), Wang and Hegele (2003) found homozygosity for a 356C-T transition in exon 2 of the CTH cDNA sequence, 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV000358891.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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; Espinós 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnonot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024