chr21-43066243-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PM1PP2PP3_StrongPP5_Very_StrongBS2_Supporting

The NM_000071.3(CBS):c.451G>A(p.Gly151Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000178 in 1,349,764 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000035 ( 1 hom., cov: 16)

Exomes 𝑓: 0.000016 ( 3 hom. )

Consequence

CBS
NM_000071.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.84

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 14 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 21-43066243-C-T is Pathogenic according to our data. Variant chr21-43066243-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 863694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.451G>A	p.Gly151Arg	missense_variant, splice_region_variant	Exon 5 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.451G>A	p.Gly151Arg	missense_variant, splice_region_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000346

AC:

AN:

115474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000918

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:

0.0000350

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248820

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1234290

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

616944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18558

American (AMR)

AF:

0.0000236

AC:

AN:

42294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21990

East Asian (EAS)

AF:

0.0000515

AC:

AN:

38862

South Asian (SAS)

AF:

0.00

AC:

AN:

76528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4432

European-Non Finnish (NFE)

AF:

0.0000160

AC:

AN:

939638

Other (OTH)

AF:

0.0000388

AC:

AN:

51602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

AF:

0.0000346

AC:

AN:

115474

Hom.:

Cov.:

AF XY:

0.0000532

AC XY:

AN XY:

56404

show subpopulations

African (AFR)

AF:

0.0000918

AC:

AN:

21798

American (AMR)

AF:

0.00

AC:

AN:

13070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2864

East Asian (EAS)

AF:

0.00

AC:

AN:

4866

South Asian (SAS)

AF:

0.00

AC:

AN:

3872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000350

AC:

AN:

57170

Other (OTH)

AF:

0.00

AC:

AN:

1628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000586

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:2

Sep 08, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Jun 19, 2020

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.451G>A variant (also known as p.G151R), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 451. This change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 151 to arginine, an amino acid with dissimilar properties. This variant has been observed in multiple individuals with homocystinuria, some of whom were homozygous or compound heterozygous with another CBS alteration (Kraus JP et al. Hum. Mutat., 1999;13:362-75; Linnebank M et al. Hum. Mutat., 2004 Oct;24:352-3; Katsushima F et al. Mol. Genet. Metab., 2006 Apr;87:323-8; Poloni S et al. Mol Genet Genomic Med, 2018 03;6:160-170). An in vitro assay involving yeast plasmids showed that cells with this alteration required glutathione supplementation to support growth, indicating severe loss of function (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). Both the nucleotide position and amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. 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. -

not provided

Pathogenic:1

Oct 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In vitro functional assays demonstrated loss of CBS enzyme activity (Mayfield et al., 2012; Katsushima et al., 2006); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 25087612, 25525159, 29352562, 22267502, 15365998, 16307898, 10338090) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 151 of the CBS protein (p.Gly151Arg). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs373782713, gnomAD 0.008%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 15365998, 16307898, 29352562). ClinVar contains an entry for this variant (Variation ID: 863694). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 20066033, 22267502). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -

CBS-related disorder

Pathogenic:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CBS c.451G>A variant is predicted to result in the amino acid substitution p.Gly151Arg. This variant was reported in the homozygous and compound heterozygous states in individuals with homocystinuria (Kraus et al. 1999. PubMed ID: 10338090; Katsushima et al. 2006. PubMed ID: 16307898; Poloni et al. 2018. PubMed ID: 29352562). Functional studies showed that this variant results in impaired enzyme activity and altered assembly of the CBS tetramer (Katsushima et al. 2006. PubMed ID: 16307898; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.0081% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Homocystinuria

Pathogenic:1

Oct 28, 2020

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.451G>A (p.Gly151Arg) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant is located in an exonic splicing region. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes or weakens a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 248820 control chromosomes. c.451G>A has been reported in the literature in multiple individuals affected with Homocystinuria (e.g. Kraus_1999, Linnebank_2004, Katsushima_2006, Poloni_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant results in severely reduced enzyme activity in-vitro when studied in E. coli or yeast models (e.g. Katsushima_2006, Singh_2010, Mayfield_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;.

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

.;.;.;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.8

H;H;H;H;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.0

D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.99

MutPred

0.98

Gain of MoRF binding (P = 0.0147);Gain of MoRF binding (P = 0.0147);Gain of MoRF binding (P = 0.0147);Gain of MoRF binding (P = 0.0147);Gain of MoRF binding (P = 0.0147);

MVP

0.94

MPC

1.2

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.070

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