rs121964972

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_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 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 criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.58

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

classic homocystinuria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000071.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

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 Pathogenic. ClinVar VariationId is 131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1058C>T	p.Thr353Met	missense_variant	Exon 12 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.1058C>T	p.Thr353Met	missense_variant	Exon 12 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000295

AC:

AN:

237672

AF XY:

0.0000383

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 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

African (AFR)

AF:

0.000701

AC:

AN:

2854

American (AMR)

AF:

0.000248

AC:

AN:

4036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1052

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

7550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

24414

Other (OTH)

AF:

0.00

AC:

AN:

2414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.000205

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Nov 08, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Feb 11, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBS: PM3:Strong, PM1, PM2, PP4:Moderate, PS3:Supporting -

Jul 23, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM1, PM2, PM3 -

Classic homocystinuria

Pathogenic:3

Feb 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Aug 31, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Homocystinuria, pyridoxine-nonresponsive

Pathogenic:1

Jul 18, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Oct 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 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). 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) has been performed 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

Jun 13, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.6

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

PromoterAI

0.095

Neutral

(source)

Varity_R

0.44

gMVP

0.82

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over