rs775992753

Positions:

chr21-43066333-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.361C>T(p.Arg121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. R121H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 9)

Exomes 𝑓: 0.000035 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.43

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 6 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066332-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 21-43066333-G-A is Pathogenic according to our data. Variant chr21-43066333-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066333-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.361C>T	p.Arg121Cys	missense_variant	5/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.361C>T	p.Arg121Cys	missense_variant	5/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251102

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135812

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000352

AC:

AN:

794602

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

412208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000517

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 23, 2018	The CBS c.361C>T (p.Arg121Cys) missense variant has been reported in three studies in which it is identified in a homozygous state in one individual and in a compound heterozygous state in a second individual in trans with a known pathogenic variant, both diagnosed with CBS deficiency (Katushima et al. 2006; Cozar et al. 2011). The variant has also been reported in a compound heterozygous state in one individual described as asymptomatic and in an additional two patient alleles of unknown zygosity (Kraus et al. 1999). In one study, the p.Arg121Cys variant was absent from 100 ethnically matched control chromosomes but is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Contradictory results were obtained in functional studies in yeast: Wei et al. (2010) describe the variant as neutral whereas Mayfield et al. (2012) describe the variant as non-functional. Six prediction algorithms predict the variant to be deleterious (Wei et al. 2010). The Arg121 residue is conserved and involved in important salt-bridge interactions with other residues (Wei et al. 2010). Based on the evidence, the p.Arg121Cys variant is classified as likely pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2023	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 22267502, 22353391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). 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. ClinVar contains an entry for this variant (Variation ID: 212842). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 21520339; Invitae). This variant is present in population databases (rs775992753, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 121 of the CBS protein (p.Arg121Cys). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2021

Not observed at significant frequency in large population cohorts (gnomAD); The p.(R121C) variant was determined to be nonfunctional in yeast complementation studies (Mayfield et al., 2021); 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: 20455263, 10338090, 21520339, 16307898, 12686134, 22267502) -

Homocystinuria

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 14, 2022

Variant summary: CBS c.361C>T (p.Arg121Cys) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme 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 1.6e-05 in 251102 control chromosomes (gnomAD). The variant, c.361C>T, has been reported in the literature in individuals affected with Homocystinuria, including one homozygote (Kraus_1999, Katsushima_2006, Cozar_2011). These data indicate that the variant is likely to be associated with disease. One publication, (Mayfield_2012), tested the function of this variant in a yeast assay and reported the variant to be non-functional, while a different functional study, also using a yeast assay, reported the variant as neutral (Wei_2010). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D;D;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

1.0

.;.;.;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

H;H;H;H;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.0

D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.98

MutPred

0.99

Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);

MVP

0.94

MPC

1.3

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over