rs148865119

Variant names:

• chr21-43072048-G-A
• rs148865119
• NM_000071.3:c.146C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43072048-G-A
• chr21-43072048-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.146C>T​(p.Pro49Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 5.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• 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 rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.146C>T	p.Pro49Leu	missense_variant	Exon 3 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.146C>T	p.Pro49Leu	missense_variant	Exon 3 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250590 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135644

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.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000260 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:6

Jul 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:4

Dec 07, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3, PP3 -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBS: PM3:Strong, PM2, PS3:Supporting -

May 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 28550590, 22612060, 9587029, 25087612, 20506325, 28421128, 20308073, 22985361, 31589614, 33848968, 25218699, 29352562, 12124992, 18280597, 32768567, 23974653, 25331909, 21520339, 23733603) -

Jan 09, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 ß-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 ß-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? Oxid Med Cell Longev. 2017;2017:8940321. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Mar 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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: 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	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.95	.;.;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;.
PrimateAI	Uncertain	0.49	T
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	D
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

Other links and lift over

dbSNP: rs148865119; hg19: chr21-44492158; COSMIC: COSV105263817; COSMIC: COSV105263817;