rs140002610

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PP2PP3_ModerateBS2

The NM_000071.3(CBS):c.394C>T(p.Arg132Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00044 ( 8 hom., cov: 13)

Exomes 𝑓: 0.00063 ( 81 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:1

Conservation

PhyloP100: 0.676

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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

MetaRNN computational evidence supports a deleterious effect, 0.903

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.394C>T	p.Arg132Cys	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.394C>T	p.Arg132Cys	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

95256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000619

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000463

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000782

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000287

AC:

AN:

250812

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000628

AC:

596

AN:

949052

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

287

AN XY:

486258

show subpopulations

African (AFR)

AF:

0.000316

AC:

AN:

15834

American (AMR)

AF:

0.0000239

AC:

AN:

41860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20474

East Asian (EAS)

AF:

0.000502

AC:

AN:

37826

South Asian (SAS)

AF:

0.0000141

AC:

AN:

71064

European-Finnish (FIN)

AF:

0.000109

AC:

AN:

36732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3656

European-Non Finnish (NFE)

AF:

0.000820

AC:

557

AN:

679148

Other (OTH)

AF:

0.000212

AC:

AN:

42458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000441

AC:

AN:

95256

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

AN XY:

46064

show subpopulations

African (AFR)

AF:

0.0000619

AC:

AN:

16166

American (AMR)

AF:

0.00

AC:

AN:

11002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2506

East Asian (EAS)

AF:

0.000463

AC:

AN:

4316

South Asian (SAS)

AF:

0.00

AC:

AN:

3068

European-Finnish (FIN)

AF:

0.000135

AC:

AN:

7434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.000782

AC:

AN:

48602

Other (OTH)

AF:

0.00

AC:

AN:

1302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

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:

0.000439

Hom.:

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic homocystinuria

Uncertain:6

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 01, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2018

Counsyl

Significance:Uncertain significance

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. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with B6-responsive and nonresponsive 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 arginine to cysteine. (I) 0251 - This variant is likely heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (26 heterozygotes, 8 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cystathionine beta-synthase domain (NCBI). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes (p.(Arg132His), p.(Arg132Ser)) have been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported many times as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be likely maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Uncertain:4Benign:1

Jun 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBS c.394C>T, p.Arg132Cys variant (rs140002610), to our knowledge, is not reported in the medical literature in CBS-related conditions but is reported in ClinVar (Variation ID: 212843). This variant is found in the non-Finnish European population with an allele frequency of 0.05% (67/128912 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.75). Due to limited information, the clinical significance of the p.Arg132Cys variant is uncertain at this time. -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBS: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 09, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a family with hallux valgus and a patient with suspected EDS in published literature; both patients harbored additional cardiogenetic variants (PMID: 33926255, 35903967); 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: 35903967, 33926255) -

not specified

Uncertain:1

Feb 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CBS c.394C>T (p.Arg132Cys) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 1044308 control chromosomes in the gnomAD database, including 89 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CBS causing Homocystinuria (0.00061 vs 0.003), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.394C>T in individuals affected with Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 212843). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

May 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R132C variant (also known as c.394C>T), located in coding exon 3 of the CBS gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the CBS protein (p.Arg132Cys). This variant is present in population databases (rs140002610, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212843). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D;D;D;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.095

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.95

.;.;.;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

M;M;M;M;.

PhyloP100

0.68

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.0

D;D;D;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.54

MVP

0.88

MPC

1.2

ClinPred

0.85

GERP RS

3.2

Varity_R

0.80

gMVP

0.76

Mutation Taster

=37/63

disease causing

(source)

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

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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