1-70415987-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 6.10

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]

ACMG classification

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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTH	NM_001902.6	c.200C>T	p.Thr67Ile	missense_variant	2/12	ENST00000370938.8
CTH	NM_001190463.2	c.200C>T	p.Thr67Ile	missense_variant	2/11
CTH	NM_153742.5	c.200C>T	p.Thr67Ile	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTH	ENST00000370938.8	c.200C>T	p.Thr67Ile	missense_variant	2/12	1	NM_001902.6	P1
CTH	ENST00000346806.2	c.200C>T	p.Thr67Ile	missense_variant	2/11	1
CTH	ENST00000411986.6	c.200C>T	p.Thr67Ile	missense_variant	2/11	2
CTH	ENST00000464926.1	n.344C>T		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1027 AN: 152158 Hom.: 2 Cov.: 33

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.: 8 AF XY: 0.00629 AC XY: 855 AN XY: 135892

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.: 71 Cov.: 28 AF XY: 0.00794 AC XY: 5760 AN XY: 725702

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.: 2 Cov.: 33 AF XY: 0.00666 AC XY: 496 AN XY: 74458

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.: 13

Bravo AF: 0.00708

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00647 AC: 786

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00921

EpiControl AF: 0.00996

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystathioninuria Pathogenic:2 Uncertain:2

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; 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -
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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CTH: PP4:Moderate, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	M;M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.67	T
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	T
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

Other links and lift over

dbSNP: rs28941785; hg19: chr1-70881670; COSMIC: COSV61008730;