chr1-70415987-C-T

Variant names:

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

Genomes: 𝑓 0.0067 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0082 ( 71 hom. )

Consequence

CTH
NM_001902.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 6.10

Variant links:

Genes affected

CTH (HGNC:2501): (cystathionine gamma-lyase) This gene encodes a cytoplasmic enzyme in the trans-sulfuration pathway that converts cystathione derived from methionine into cysteine. Glutathione synthesis in the liver is dependent upon the availability of cysteine. Mutations in this gene cause cystathioninuria. Alternative splicing of this gene results in three transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

CTH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.023492247).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 12	ENST00000370938.8	NP_001893.2	P32929-1
CTH	NM_001190463.2 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 11		NP_001177392.1	P32929-3
CTH	NM_153742.5 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 11		NP_714964.2	P32929-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTH	ENST00000370938.8 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 12	1	NM_001902.6	ENSP00000359976.3	P32929-1
CTH	ENST00000346806.2 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 11	1		ENSP00000311554.2	P32929-2
CTH	ENST00000411986.6 link	c.200C>T	p.Thr67Ile	missense_variant	Exon 2 of 11	2		ENSP00000413407.2	P32929-3
CTH	ENST00000464926.1 link	n.344C>T		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.00675

AC:

1027

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00939

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00648

AC:

1628

AN:

251408

Hom.:

AF XY:

0.00629

AC XY:

855

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00766

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.00936

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00816

AC:

11900

AN:

1458344

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

5760

AN XY:

725702

show subpopulations

Gnomad4 AFR exome

AF:

0.00174

Gnomad4 AMR exome

AF:

0.00796

Gnomad4 ASJ exome

AF:

0.00843

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00166

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.00943

Gnomad4 OTH exome

AF:

0.00720

GnomAD4 genome

AF:

0.00674

AC:

1027

AN:

152276

Hom.:

Cov.:

AF XY:

0.00666

AC XY:

496

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.0149

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00274

Gnomad4 NFE

AF:

0.00940

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00844

Hom.:

Bravo

AF:

0.00708

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00647

AC:

786

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.00921

EpiControl

AF:

0.00996

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystathioninuria

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CTH: PP4:Moderate, PS3:Supporting -

CTH-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2024

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;D;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.5

M;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.027

D;D;D

Polyphen

1.0, 0.99

.;D;D

Vest4

0.87

MVP

0.99

MPC

0.66

ClinPred

0.063

GERP RS

5.5

Varity_R

0.94

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over