Variant rs121964972 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000071.3(CBS):c.1058C>T(p.Thr353Met) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T353T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.58

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.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 21-43060528-G-A is Pathogenic according to our data. Variant chr21-43060528-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43060528-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-43060528-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.1058C>T	p.Thr353Met	missense_variant	12/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.1058C>T	p.Thr353Met	missense_variant	12/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000295

AC:

AN:

237672

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130450

show subpopulations

Gnomad AFR exome

AF:

0.000392

Gnomad AMR exome

AF:

0.0000291

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:

0.00

GnomAD4 exome

AF:

0.0000633

AC:

AN:

47412

Hom.:

Cov.:

AF XY:

0.0000791

AC XY:

AN XY:

25288

show subpopulations

Gnomad4 AFR exome

AF:

0.000701

Gnomad4 AMR exome

AF:

0.000248

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	CBS: PM3:Strong, PM1, PM2, PP4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	Functional studies have demonstrated that this variant results in reduced enzymatic activity (Mayfield et al., 2012); This variant is associated with the following publications: (PMID: 14635102, 20066033, 17540596, 18849566, 9156316, 23685761, 21520339, 22267502, 21626167, 24211323, 16479318, 12124992, 16205833, 31589614, 23812867) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 23, 2020	PS3, PM1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2013	- -

Classic homocystinuria

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 21, 2014	- -

Homocystinuria, pyridoxine-nonresponsive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 18, 2017

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2021

The c.1058C>T (p.T353M) alteration is located in exon 12 (coding exon 10) of the CBS gene. This alteration results from a C to T substitution at nucleotide position 1058, causing the threonine (T) at amino acid position 353 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (8/269064) total alleles studied. The highest observed frequency was 0.03% (7/24008) of African alleles. This alteration has been reported in the homozygous state and in trans with a second CBS alteration in patients with homocystinuria across various ethnicities (Kruger, 2003; Lee, 2005; Karaca, 2014; Poloni, 2018). In vitro functional studies of this alteration showed a substantial reduction in CBS activity and low growth in yeast assays (Kruger, 2003; Mayfield, 2012). In vitro expression studies of this alteration also demonstrated reduced enzyme activity in COS7 and NIH3T3 cells (Lee, 2005). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 353 of the CBS protein (p.Thr353Met). This variant is present in population databases (rs121964972, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9156316, 11774777, 12124992, 14635102, 16205833, 16479318, 21520339, 23812867). ClinVar contains an entry for this variant (Variation ID: 131). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CBS protein function. Experimental studies have shown that this missense change affects CBS function (PMID: 9156316, 14635102, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 13, 2022

Variant summary: CBS c.1058C>T (p.Thr353Met) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 237672 control chromosomes (gnomAD). c.1058C>T has been reported in the literature in multiple individuals affected with Homocystinuria (e.g. Dawson_1997, Trondle_2001, Kruger_2003, Lee_2005). These data indicate that the variant is very likely to be associated with disease. The variants' impact on protein function was evaluated in several different publications using recombinant protein recovered from E. coli cultures (Dawson_1997), yeast (Kruger_2003) and human cell lines (Lee_2005). In all instances, the variant protein had <10% of normal activity. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D;D

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

.;.;.;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.88

L;L;L;L

MutationTaster

Benign

0.016

A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.059

B;B;B;B

Vest4

0.47

MVP

0.85

MPC

0.70

ClinPred

0.14

GERP RS

3.2

Varity_R

0.44

gMVP

0.82

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