rs786204495

Positions:

chr21-43060450-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.1136G>A(p.Arg379Gln) variant causes a missense change. In-silico tool predicts a pathogenic 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. R379W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 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: 5.78

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 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43060451-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 21-43060450-C-T is Pathogenic according to our data. Variant chr21-43060450-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43060450-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.1136G>A	p.Arg379Gln	missense_variant	12/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.1136G>A	p.Arg379Gln	missense_variant	12/17	1	NM_000071.3	ENSP00000381231	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249472

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135332

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

24284

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

13382

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 11, 2014	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2015

The R379Q variant in the CBS gene was reported in one Spanish patient with severe homocystinuria, whoalso carried a second CBS variant, 1566delG (Urreizti et al., 2003). The R379Q substitution was absent form50 healthy, ethnically matched controls (Urreizti et al., 2003), and was also not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. R379Q is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties, albeitthis residue is not conserved across species. Furthermore, a missense variant in the same residue (R379W)and in nearby residues (C370Y, V371M, D376N, K384E, K384N) have been reported in the Human GeneMutation Database in association with homocystinuria (Stenson et al., 2014), supporting the functionalimportance of this residue and region of the protein. Moreover, in vitro expression in e.coli and functionalassays demonstrated that the presence of R379Q completely abolishes enzyme function, most likely due to alack of monomers to form functional tetramers (Urreizti et al., 2006). In summary, R379Q in the CBS gene is interpreted as a pathogenic variant. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 379 of the CBS protein (p.Arg379Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CBS function (PMID: 16429402). 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: 188825). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 16479318, 21520339). This variant is present in population databases (rs763036586, gnomAD 0.002%). -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 28, 2024

Variant summary: CBS c.1136G>A (p.Arg379Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249472 control chromosomes (gnomAD). c.1136G>A has been reported in the literature in several individuals affected with Homocystinuria (e.g. Urreizti_2003, Van Hove_2019, Kaur_2020, Gorukmez_2023). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1135C>T, p.Arg379Trp), supporting the critical relevance of codon 379 to CBS protein function. The following publications have been ascertained in the context of this evaluation (PMID: 12815602, 33057012, 36964972, 30873612). ClinVar contains an entry for this variant (Variation ID: 188825). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;D;D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;.;.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.011

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.71

P;P;P;P

Vest4

0.80

MutPred

0.84

Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);Loss of MoRF binding (P = 0.0274);

MVP

0.92

MPC

0.96

ClinPred

0.98

GERP RS

4.0

Varity_R

0.88

gMVP

0.86

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