Variant 21-43072048-G-A details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000071.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 21-43072048-G-A is Pathogenic according to our data. Variant chr21-43072048-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43072048-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.146C>T	p.Pro49Leu	missense_variant	3/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.146C>T	p.Pro49Leu	missense_variant	3/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000152

AC:

AN:

250590

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135644

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000260

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2019	The p.Pro49Leu variant in CBS has been reported in 7 compound heterozygous and 1 homozygous individuals with mild homocystinuria, and segregated with disease in 1 affected relative (Alcaide 2015, Cozar 2011, Evangelisti 2009, Gaustadnes 2002, Mendes 2014, Poloni 2018). In addition, it segregated with thromboembolic episodes in one family without the associated ocular, skeletal, or CNS abnormalities (Stabler 2013). It was also found in an asymptomatic sibling with hyperhomocysteinemia and hypermethioninemia but had no clinical sign of classical homocystinuria and had given birth to three healthy offspring without complications (Cozar 2011). It has also been identified in 0.031% (40/128366) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 212872). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro and in vivo functional studies support a mild impact on protein function (Alcaide 2015, Cozar 2011, Hnizda 2012, Kozich 2010, Mendes 2014, Vicente 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for mild homocystinuria. ACMG/AMP Criteria applied: PM3_Very Strong, PP1, PS3_Supporting. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 21, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 09, 2020	The CBS c.146C>T; p.Pro49Leu variant (rs148865119) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with homocystinuria, but is associated with a mild clinical phenotype (Cozar 2011, De Franchis 1998, Gaustadnes 2002, Mendes 2014, Stabler 2013). This variant is reported in ClinVar (Variation ID: 212872), and is found in the general population with an overall allele frequency of 0.015% (42/281978 alleles) in the Genome Aggregation Database. The proline at codon 49 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate a mild decrease in protein expression and function (Cozar 2011, Mendes 2014, Pey 2013, Vicente 2017). Based on available information, this variant is considered to be likely pathogenic. References: Cozar M et al. Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. Hum Mutat. 2011 Jul;32(7):835-42. De Franchis R et al. Clinical aspects of cystathionine beta-synthase deficiency: how wide is the spectrum? The Italian Collaborative Study Group on Homocystinuria. Eur J Pediatr. 1998 Apr;157 Suppl 2:S67-70. Gaustadnes M et al. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26. Mendes MI et al. Reduced response of Cystathionine Beta-Synthase (CBS) to S-Adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients. J Inherit Metab Dis. 2014 Mar;37(2):245-54. Pey AL et al. Human cystathionine ÃŸ-synthase (CBS) contains two classes of binding sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM. Biochem J. 2013 Jan 1;449(1):109-21. Stabler SP et al. Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 2013;11:149-63. Vicente JB et al. A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine ÃŸ-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? Oxid Med Cell Longev. 2017;2017:8940321. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2020	PS3, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2023	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: 29352562, 23974653, 10338090, 28550590, 22612060, 9587029, 25087612, 20506325, 28421128, 20308073, 25331909, 22985361, 31589614, 32768567, 33848968, 21520339, 12124992, 25218699, 18280597, 23733603) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CBS: PM3:Strong, PM2, PS3:Supporting -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The p.P49L pathogenic mutation (also known as c.146C>T), located in coding exon 1 of the CBS gene, results from a C to T substitution at nucleotide position 146. The proline at codon 49 is replaced by leucine, an amino acid with similar properties. This mutation was detected in a patient with homocystinuria, who also had an in-frame deletion and was pyridoxine responsive (De Franchis R, et al. Eur J Pediatr. 1998;157:S67-70). In addition this alteration was observed in conjunction with a splice site mutation in a patient who presented with deep vein thrombosis along with cardiac, ocular, and skeletal symptoms; however, information on phase was not provided (Evangelisti L, Int. J. Cardiol. 2009 May; 134(2):251-4). This alteration has been reported in an individual with a history of severe thoracic aortic aneurysm, but who also harbored an ACTA2 variant (Landis BJ et al. J Cardiovasc Transl Res, 2017 May). In another study, this mutation was detected in a mildly affected patient and his asymptomatic sister, both of whom carried a mild mutation in the other CBS allele. Functional studies showed that p.P49L was associated with mildly reduced enzyme activity (about 75% of the wild type) (Cozar M, et al. Hum Mutat. 2011;32(7):835-842). A further study determined that protein expression in fibroblasts from a homozygous individual were decreased. In addition, both protein levels and enzymatic activity were reduced to approximately 40% when expressed in vitro. However, the protein maintained normal response levels to its activator protein (Mendes J. Inherit. Metab Dis. 2014;37(2):25-254). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 49 of the CBS protein (p.Pro49Leu). This variant is present in population databases (rs148865119, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9587029, 12124992, 18280597, 21520339, 23733603, 23974653, 25218699, 29352562). 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: 212872). 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 have shown that this missense change affects CBS function (PMID: 21520339, 22985361, 23974653). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D;D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;.;.;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.4

D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

0.98

D;D;D;D;.

Vest4

0.79

MVP

0.94

MPC

0.45

ClinPred

0.55

GERP RS

5.6

Varity_R

0.89

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

21-43072048-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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