rs773734233

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PP2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.700G>A(p.Asp234Asn) 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. D234D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000086 ( 1 hom., cov: 15)

Exomes 𝑓: 0.000019 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.65

Publications

10 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 15 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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, 0.97

PP5

Variant 21-43065239-C-T is Pathogenic according to our data. Variant chr21-43065239-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212852.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.700G>A	p.Asp234Asn	missense_variant	Exon 8 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.700G>A	p.Asp234Asn	missense_variant	Exon 8 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000860

AC:

AN:

127908

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000389

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:

0.00176

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251422

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000193

AC:

AN:

1293816

Hom.:

Cov.:

AF XY:

0.0000186

AC XY:

AN XY:

644588

show subpopulations

African (AFR)

AF:

0.0000946

AC:

AN:

31702

American (AMR)

AF:

0.0000465

AC:

AN:

42968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23024

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.000162

AC:

AN:

80394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

0.00000517

AC:

AN:

967296

Other (OTH)

AF:

0.0000368

AC:

AN:

54398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000860

AC:

AN:

127908

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

62044

show subpopulations

African (AFR)

AF:

0.0000846

AC:

AN:

35474

American (AMR)

AF:

0.000389

AC:

AN:

12850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2948

East Asian (EAS)

AF:

0.00

AC:

AN:

5068

South Asian (SAS)

AF:

0.00

AC:

AN:

3922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56168

Other (OTH)

AF:

0.00176

AC:

AN:

1708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000420

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:1

Feb 10, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Mar 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that D234N expression in E. coli cells reduces CBS enzyme activity and D234N expression in Hek 293 cells leads to less soluble and fewer properly assembled subunits, suggesting D234N may lead to an unstable protein that is less able to assemble into a functional enzyme (Casique et al., 2014); 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: 10338090, 14972327, 22267502, 20303981, 19914636, 16786517, 23981774) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Sep 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 234 of the CBS protein (p.Asp234Asn). This variant is present in population databases (rs773734233, gnomAD 0.006%). This missense change has been observed in individual(s) with homocystinuria (PMID: 14972327, 16786517; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212852). 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: 22267502, 23981774). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Jun 26, 2016

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.700G>A (p.Asp234Asn) variant causes a missense change located in the CBS N-terminal catalytic domain at a position that is conserved across species (De Luca et al., 2004). This involves a conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "damaging" outcome, which is further supported with functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60671), which does not exceed the estimated maximal expected allele frequency for a pathogenic CBS variant of 1/328 (0.0030414). The variant of interest has been reported in multiple affected individuals via publications including 2 homozygous individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

.;.;.;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;L;L;L

PhyloP100

6.6

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.022

D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.89

MutPred

0.79

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.94

MPC

1.1

ClinPred

0.88

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.85

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over