21-43068592-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP2PP3_Strong

The NM_000071.3(CBS):c.233C>G(p.Pro78Arg) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P78P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 5)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 8.50

Publications

11 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 5 ACMG points.

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, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.233C>G	p.Pro78Arg	missense_variant	Exon 4 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.233C>G	p.Pro78Arg	missense_variant	Exon 4 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251194

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

365770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

200272

African (AFR)

AF:

0.00

AC:

AN:

8810

American (AMR)

AF:

0.00

AC:

AN:

19620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11910

East Asian (EAS)

AF:

0.00

AC:

AN:

26512

South Asian (SAS)

AF:

0.00

AC:

AN:

45368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1550

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

210342

Other (OTH)

AF:

0.00

AC:

AN:

20078

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:1

Sep 26, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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. -

not specified

Uncertain:1

Mar 15, 2023

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.233C>G (p.Pro78Arg) results in a non-conservative amino acid change in 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 4e-06 in 251194 control chromosomes. c.233C>G has been reported in the literature as a complex allele in cis alongside c.306G>C (p.Lys102Asn) in a biparentally confirmed compound heterozygous genotype with c.715G>A (p.E239K) (not reported in ClinVar) in trans in two affected siblings with features of Homocystinuria and their unaffected brother (deFranchis_1994). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria. Multiple publications report conflicting variant specific experimental evidence evaluating an impact on protein function in vitro (example, deFranchis_1994, Sen_2007, Mayfield_2012, Hnizda_2012, Melenovska_2015, Majtan_2010). The most pronounced variant effect results in CBS activities ranging from 10%-<30%, 30-50% or >50-90% of normal depending upon the expression systems and kinetic parameters evaluated (Ecoli, Yeast, CHO-K1 cells). The complex allele of Pro78Arg+Lys102Asn expressed in cis had 0% activity (deFranchis_1994). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jun 21, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P78R variant (also known as c.233C>G), located in coding exon 2 of the CBS gene, results from a C to G substitution at nucleotide position 233. The proline at codon 78 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported as occurring in cis with p.K102N as a complex allele [P78R:K102N] in three siblings with homocystinuria who had p.E239K in trans. The same study also reported that the complex allele led to abolished CBS activity, while the individual variants resulted in reduced activity (de Franchis R et al. Hum. Mol. Genet., 1994 Jul;3:1103-8). The double variant was revealed to lose AdoMet-dependent regulation (Sen S et al. Biochemistry, 2007 Apr;46:4110-6). In addition, follow-up research suggested that the reduced activity of the individual variants might be rescued to some extent by improving protein folding (Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Kopecká J et al. J. Inherit. Metab. Dis., 2011 Feb;34:39-48). However, in yeast assays, this alteration was described to behave similarly to wildtype (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23), and no obvious biophysical difference has been observed (Majtan T et al. J. Biol. Chem., 2010 May;285:15866-73; Hnízda A et al. Biochemistry, 2012 Jun;51:4755-63; Pey AL et al. Biochem. J., 2013 Jan;449:109-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Uncertain:1

Jun 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 78 of the CBS protein (p.Pro78Arg). This variant is present in population databases (rs786204608, gnomAD 0.0009%). This missense change has been observed in individual(s) with CBS deficiency (PMID: 7967489). ClinVar contains an entry for this variant (Variation ID: 188988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 7981678, 20308073, 22612060, 25331909). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;D;D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;.;.;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;M;M;.

PhyloP100

8.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.7

D;D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.025

D;D;D;D;D

Sift4G

Benign

0.090

T;T;T;T;T

Polyphen

0.98

D;D;D;D;.

Vest4

0.90

MutPred

0.75

Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);

MVP

0.93

MPC

1.0

ClinPred

0.99

GERP RS

4.8

Varity_R

0.81

gMVP

0.81

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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