21-43066353-G-A

Variant names:

• chr21-43066353-G-A
• rs121964964
• NM_000071.3:c.341C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP2 PP5_Very_Strong BS2_Supporting

The NM_000071.3(CBS):​c.341C>T​(p.Ala114Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 7)
  • Exomes 𝑓: 0.00011 (6 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 8.69
• Publications: 35 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066354-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 429655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP5: Variant 21-43066353-G-A is Pathogenic according to our data. Variant chr21-43066353-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 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	c.341C>T	p.Ala114Val	missense_variant	Exon 5 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.341C>T	p.Ala114Val	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.0000504 AC: 3 AN: 59574 Hom.: 0 Cov.: 7

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000139

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: 0.0000620

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000211 AC: 53 AN: 251024 AF XY: 0.000221

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 84 AN: 754022 Hom.: 6 Cov.: 10 AF XY: 0.000102 AC XY: 40 AN XY: 391174

African (AFR) AF: 0.00 AC: 0 AN: 14126

American (AMR) AF: 0.000156 AC: 6 AN: 38450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18816

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35614

South Asian (SAS) AF: 0.00 AC: 0 AN: 66212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2728

European-Non Finnish (NFE) AF: 0.000135 AC: 69 AN: 509476

Other (OTH) AF: 0.0000842 AC: 3 AN: 35632

GnomAD4 genome AF: 0.0000503 AC: 3 AN: 59606 Hom.: 0 Cov.: 7 AF XY: 0.0000353 AC XY: 1 AN XY: 28290

African (AFR) AF: 0.00 AC: 0 AN: 7982

American (AMR) AF: 0.000139 AC: 1 AN: 7194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3092

South Asian (SAS) AF: 0.00 AC: 0 AN: 1692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 112

European-Non Finnish (NFE) AF: 0.0000620 AC: 2 AN: 32262

Other (OTH) AF: 0.00 AC: 0 AN: 802

Alfa AF: 0.000184 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: 0.000264 AC: 32

EpiCase AF: 0.000382

EpiControl AF: 0.000889

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:10

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PS4_moderate,PM2,PM3,PP3 -

Mar 01, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 16, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5. -

Oct 15, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with B6-responsive and non-responsive types homocystinuria, and hyperhomocysteinemic thrombosis (MIM#236200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated PALP domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change at the same residue (p.Ala114Thr) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times, in patients with homocystinuria (ClinVar, LOVD, PMID: 32232970). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been proven to have mild effects on function, reducing enzyme activity, tetramer formation and protein instability (PMID: 22069143). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM3_verystrong, PP3, PP4 -

May 20, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies have shown p.(A114V) leads to protein misfolding and instability compared to wild-type alleles (PMID: 22069143, 20506325); 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: 22612060, 22267502, 22985361, 25331909, 22069143, 20308073, 14722927, 10408774, 8353501, 28097321, 25087612, 12686134, 20506325, 20490928, 11748855, 20066033, 16307898, 16479318, 7762555, 31589614, 11359213, 34426522, 7967489, 39041895, 14739681, 37460657, 38532509) -

Feb 14, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PS3, PP3, PS4, PM2_SUP -

Feb 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CBS c.341C>T; p.Ala114Val variant (rs121964964) has been detected in both a compound heterozygous form together with another CBS variant, or with no second CBS variant identified, in several patients with a clinical diagnosis of homocystinuria (Kozich 1993, Sebastio 1995, Kraus 1999, de Franchis 1999, Moat 2005). This variant is reported as pathogenic in ClinVar (Variation ID: 119) and is found in the general population with an overall allele frequency of 0.02% (61/282,364 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.88). This variant was reported to be compatible with pyridoxine responsiveness in several patients (Kraus 1999). This variant is located in the dimer interface of the active core (Meier 2003), and in vitro studies of this variant have shown an enzyme activity in the range of 46.2-76.9% of wild-type CBS (de Franchis 1999; Hnizda 2012). Functional studies found the protein was determined to be relatively stable (deFranchis 1999, Hnizda 2012) and able to form tetramers up to approximately 74% of that observed in controls (Janosik 2001, Hnizda 2012). Based on these observations, we have classified p.Ala114Val as a mild pathogenic variant. References: de Franchis R et al. Four novel mutations in the cystathionine beta-synthase gene: effect of a second linked mutation on the severity of the homocystinuric phenotype. Hum Mutat. 1999;13(6):453-7. PMID: 10408774. Hnizda A et al. Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Inherit Metab Dis. 2012 May;35(3):469-77. PMID: 22069143. Janosik M et al. Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet. 2001 Jun;68(6):1506-13. PMID: 11359213. Kozich V et al. Molecular defect in a patient with pyridoxine-responsive homocystinuria. Hum Mol Genet. 1993 Jun;2(6):815-6. PMID: 8353501. Kraus JP et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13(5):362-75. PMID: 10338090. Meier M et al. Structural insights into mutations of cystathionine beta-synthase. Biochim Biophys Acta. 2003 Apr 11;1647(1-2):206-13. PMID: 12686134. Moat SJ et al. The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat. 2004 Feb;23(2):206. PMID: 14722927. Sebastio G et al. The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995 Jun;56(6):1324-33. PMID: 7762555. -

Homocystinuria, pyridoxine-responsive Pathogenic:1

Jun 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Aug 04, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A114V pathogenic mutation (also known as c.341C>T), located in coding exon 3 of the CBS gene, results from a C to T substitution at nucleotide position 341. The alanine at codon 114 is replaced by valine, an amino acid with similar properties. This variant has been reported to co-occur with other CBS pathogenic and likely pathogenic variants in several individuals with homocystinuria, including at least one case where the variants were confirmed in trans (Kozich V et al. Hum. Mol. Genet., 1993 Jun;2:815-6; Sebastio G et al. Am. J. Hum. Genet., 1995 Jun;56:1324-33; Janos&iacute;k M et al. Am. J. Hum. Genet., 2001 Jun;68:1506-13; Orend&aacute;c M et al. J Inherit Metab Di . 2003 ;26(8):761-73; Katsushima F et al. Mol Genet Metab. 2006 Apr;87(4):323-8; Sweetser DA et al. N Engl J Med. 2016 11;375(19):1879-1890). Functional studies demonstrated reduced enzyme activity likely due to impaired folding and/or tetramer formation (Janos&iacute;k M et al. Am. J. Hum. Genet., 2001 Jun;68:1506-13; Kozich V et al. Hum. Mol. Genet., 1993 Jun;2:815-6; Majtan T et al. J. Biol. Chem., 2010 May;285:15866-73). 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. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 114 of the CBS protein (p.Ala114Val). This variant is present in population databases (rs121964964, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria due to cystathionine-beta synthase (CBS) deficiency (PMID: 7762555, 8353501). ClinVar contains an entry for this variant (Variation ID: 119). 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: 20490928, 20506325, 22069143, 22267502, 22612060). For these reasons, this variant has been classified as Pathogenic. -

CBS-related disorder Pathogenic:1

Dec 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CBS c.341C>T variant is predicted to result in the amino acid substitution p.Ala114Val. This variant has been reported in the homozygous state and the heterozygous state (along with a second causative variant) in individuals with pyridoxine-responsive homocystinuria (Kozich et al. 1993. PubMed ID: 8353501; Reuter et al. 2017. PubMed ID: 28097321, eTable 1 and 2). Experimental studies using recombinant bacterial systems suggest that this variant leads to mild protein unfolding, mild protein instability, and reduced enzymatic activity (Kozich et al. 2010. PubMed ID: 20506325, Table 1; Hnízda et al. 2011. PubMed ID: 22069143; Hnízda et al. 2012. PubMed ID: 22612060). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Homocystinuria Pathogenic:1

Jan 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 c.341C>T in CBS gene is a missense variant that involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC ans ESP projects at an allele frequency of 0.027%. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in CBS (0.3%).suggesting this variant is not a common polymorphism. The variant has been reported in several affected individuals presented with features suggestive of Cystathionine--synthase deficiency. Functional studies performed in bacteria-based system showed slight misfolding of the recombinant protein and low enzymatic activity. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers.Taking together, the variant was classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;.;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.77	N;N;N;N;.
PhyloP100		8.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.017	D;D;D;D;T
Sift4G	Uncertain	0.020	D;D;D;D;T
Polyphen		0.97	D;D;D;D;.
Vest4		0.97
MVP		0.91
MPC		0.75
ClinPred		0.22	T
GERP RS		5.4
Varity_R		0.66
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121964964; hg19: chr21-44486463; COSMIC: COSV61442591; COSMIC: COSV61442591;