rs121964973

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.572C>T(p.Thr191Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 4)

Exomes 𝑓: 0.000062 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 8.36

Variant links:

Genes affected

CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

CBS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 21-43065481-G-A is Pathogenic according to our data. Variant chr21-43065481-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065481-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.572C>T	p.Thr191Met	missense_variant	Exon 7 of 17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.572C>T	p.Thr191Met	missense_variant	Exon 7 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

17072

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249042

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.0000624

AC:

AN:

416838

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

220480

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000746

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000217

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

17072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

7940

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:7

Sep 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 27, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting -

Sep 27, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.99 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003896 /PMID: 2961848 /3billion dataset). Different missense changes at the same codon (p.Arg178Cys, p.Arg178Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003897, VCV000003912 /PMID: 1833974, 2137287). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Oct 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., 2012; Hnzda A et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16429402, 15993874, 1281560, 29352562, 33335839, 26667307, 10338090, 20506325, 22267502, 27681349, 31589614, 16479318, 22069143, 16470595) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBS: PP1:Strong, PM2, PM3, PS3:Moderate, PP3 -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Apr 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T191M pathogenic mutation (also known as c.572C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at nucleotide position 572. The threonine at codon 191 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the homozygous state, or in conjunction with another CBS variant, in multiple individuals with CBS-related homocystinuria (Urreizti R et al. Hum Mutat, 2003 Jul;22:103; Bermúdez M et al. Hum Mutat, 2006 Mar;27:296; Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Oliveira Santos M et al. BMJ Case Rep, 2016 Sep;2016:[ePub ahead of print]; Martín-Rivada Á et al. JIMD Rep, 2022 Mar;63:146-161). Functional assays showed reduction in enzyme activity (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Homocystinuria, pyridoxine-nonresponsive

Pathogenic:1

Jan 07, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 191 of the CBS protein (p.Thr191Met). This variant is present in population databases (rs121964973, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 15993874, 16470595, 16479318, 25218699). ClinVar contains an entry for this variant (Variation ID: 132). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 10338090, 16429402, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Jun 05, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the protein (Hnizda_2012) and is predicted to be damaging by 5/5 in silico tools. Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012). This variant is absent in 117282 control chromosomes from ExAC. This variant is a known common pathogenic variant that causes homocystinuria. It is highly prevalent in homocystinuric patients from Spain, Portugal and South America. Genotype-phenotype correlation study show this variant leads to non-responsiveness to vitamin B6. One clinical laboratory and one reputable database (via ClinVar) have have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

CBS-related disorder

Pathogenic:1

Jan 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CBS c.572C>T variant is predicted to result in the amino acid substitution p.Thr191Met. This variant has been reported in individuals with homocystinuria (Kraus et al. 1999. PubMed ID: 10338090; Urreizti et al. 2003. PubMed ID: 12815602; Porto et al. 2005. PubMed ID: 15993874; Bermudez et al. 2006. PubMed ID: 16470595; Urreizti et al. 2006. PubMed ID: 16479318; Alcaide et al. 2014. PubMed ID: 25218699). Functional studies indicate that this amino acid change decreases the native folding of the encoded protein, substantially decreasing enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2011. PubMed ID: 22069143; Alcaide et al. 2014. PubMed ID: 25218699). The p.Thr191Met substitution is considered a pyridoxine non-responsive mutation (Alcaide et al. 2014. PubMed ID: 25218699). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132/). Given the evidence, we interpret CBS c.572C>T (p.Thr191Met) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

.;.;.;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H;H;H

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.7

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.97

MutPred

0.90

Loss of phosphorylation at T191 (P = 0.0306);Loss of phosphorylation at T191 (P = 0.0306);Loss of phosphorylation at T191 (P = 0.0306);Loss of phosphorylation at T191 (P = 0.0306);

MVP

0.95

MPC

1.1

ClinPred

1.0

GERP RS

3.7

Varity_R

0.92

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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