chr21-43066264-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.430G>A(p.Glu144Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000762 in 1,312,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 15)

Exomes 𝑓: 0.0000067 ( 1 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.84

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 21-43066264-C-T is Pathogenic according to our data. Variant chr21-43066264-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066264-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.430G>A	p.Glu144Lys	missense_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.430G>A	p.Glu144Lys	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111250

Hom.:

Cov.:

show subpopulations

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:

0.0000360

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250114

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135412

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000666

AC:

AN:

1201460

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

602398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.0000787

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000110

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111250

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

54076

show subpopulations

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:

0.0000360

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:4

Nov 09, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000071.2(CBS):c.430G>A(E144K) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. E144K has been observed in cases with relevant disease (PMID: 14722927, 12124992, 11359213, 7611293, 33057012). Functional assessments of this variant are available in the literature (PMID: 25331909, 22267502, 20506325, 20490928). E144K has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000071.2(CBS):c.430G>A(E144K) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Suma Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu144Lys variant in CBS has been reported in at least 10 individuals with homocystinuria (Shih 1995 PMID: 7611293, Gordon 1998 PMID: 10215408, Gaustadnes 2002 PMID: 12124992, Kaur 2020 PMID: 33057012). It has also been identified in 0.0036% (2/55574) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 122). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function as the expression of enzymatic activity was found to be <1% of wild type in E. Coli and yeast (Gordon 1998 PMID: 10215408, Mayfield 2012 PMID: 22267502). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.) -

not provided

Pathogenic:4

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect through decreased enzyme levels (Kozich et al., 2010); 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: 15365998, 14722927, 22267502, 9156316, 31301157, 7611293, 11748855, 11359213, 25331909, 12124992, 20567906, 10215408, 20506325, 33057012) -

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Homocystinuria, pyridoxine-responsive

Pathogenic:1

Jul 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 144 of the CBS protein (p.Glu144Lys). This variant is present in population databases (rs121964966, gnomAD 0.01%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7611293, 10215408, 12124992, 33057012). 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: 122). 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) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 20506325, 22267502, 25331909). For these reasons, this variant has been classified as Pathogenic. -

CBS-related disorder

Pathogenic:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CBS c.430G>A variant is predicted to result in the amino acid substitution p.Glu144Lys. This variant has been reported in the heterozygous state with a second causative or likely causative variant in multiple patients with cystathionine beta-synthase deficiency (e.g., Shih et al. 1995. PubMed ID: 7611293; Janosík et al. 2001. PubMed ID: 11359213; Gaustadnes et al. 2002. PubMed ID: 12124992; Kaur et al. 2020. PubMed ID: 33057012). Functional studies have shown that the p.Glu144Lys change essentially abolishes CBS activity in E. coli and yeast cells (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502), although studies using CHO-K1 cells were conflicting (Melenovská et al. 2014. PubMed ID: 25331909). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Homocystinuria

Pathogenic:1

Apr 28, 2023

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.430G>A (p.Glu144Lys) results in a conservative amino acid change located in the pyridoxal-phosphate dependent enzyme (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 2.8e-05 in 250114 control chromosomes (gnomAD). c.430G>A has been reported in the literature as a compound heterozygous genotype in trans with other pathogenic alleles in multiple individuals affected with Homocystinuria (e.g. Shih_1995, Gordon_1998, Janosik_2001, Guastadnes_2002,Kozich_2010). These data indicate that the variant is very likely to be associated with disease. In some of these cases, the variant has been reported to co-occur in cis with another variant which has conflicting interpretations of pathogenicity (i.e. c.463G>A, p.A155T in Janosik_2001). Multiple publications report contrasting experimental evidence evaluating an impact on protein function. The variant was found to result in significantly reduced enzyme activity in yeast and bacterial cell lines (e.g. Gordon_1998, Kozich_2010, Mayfield_2012) but had no significant damaging effect in experiments in a mammalian cell line (Melenovska_2014). The following publications have been ascertained in the context of this evaluation (PMID: 12124992, 10215408, 11359213, 20506325, 22267502, 25331909, 7611293). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=5)/likely pathogenic (n=1). 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

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D;D;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

1.0

.;.;.;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;H;H;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.0

D;D;D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.99

MutPred

0.95

Gain of methylation at E144 (P = 0.0066);Gain of methylation at E144 (P = 0.0066);Gain of methylation at E144 (P = 0.0066);Gain of methylation at E144 (P = 0.0066);Gain of methylation at E144 (P = 0.0066);

MVP

0.90

MPC

1.2

ClinPred

1.0

GERP RS

4.3

Varity_R

0.99

gMVP

0.99

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