chr1-70415987-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2
The NM_001902.6(CTH):c.200C>T(p.Thr67Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00803 in 1,610,620 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001902.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CTH | NM_001902.6 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 12 | ENST00000370938.8 | NP_001893.2 | |
CTH | NM_001190463.2 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 11 | NP_001177392.1 | ||
CTH | NM_153742.5 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 11 | NP_714964.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CTH | ENST00000370938.8 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 12 | 1 | NM_001902.6 | ENSP00000359976.3 | ||
CTH | ENST00000346806.2 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 11 | 1 | ENSP00000311554.2 | |||
CTH | ENST00000411986.6 | c.200C>T | p.Thr67Ile | missense_variant | Exon 2 of 11 | 2 | ENSP00000413407.2 | |||
CTH | ENST00000464926.1 | n.344C>T | non_coding_transcript_exon_variant | Exon 2 of 6 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00675 AC: 1027AN: 152158Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00648 AC: 1628AN: 251408Hom.: 8 AF XY: 0.00629 AC XY: 855AN XY: 135892
GnomAD4 exome AF: 0.00816 AC: 11900AN: 1458344Hom.: 71 Cov.: 28 AF XY: 0.00794 AC XY: 5760AN XY: 725702
GnomAD4 genome AF: 0.00674 AC: 1027AN: 152276Hom.: 2 Cov.: 33 AF XY: 0.00666 AC XY: 496AN XY: 74458
ClinVar
Submissions by phenotype
Cystathioninuria Pathogenic:2Uncertain:2
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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. -
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not provided Uncertain:2
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CTH: PP4:Moderate, PS3:Supporting -
CTH-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at