21-43062358-G-T

Variant names:

Variant summary

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

The NM_000071.3(CBS):c.992C>A(p.Ala331Glu) 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. A331V) 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:4

Conservation

PhyloP100: 6.80

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 helix (size 14) in uniprot entity CBS_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43062358-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 21-43062358-G-T is Pathogenic according to our data. Variant chr21-43062358-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062358-G-T is described in Lovd as [Pathogenic]. Variant chr21-43062358-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.992C>A	p.Ala331Glu	missense_variant	Exon 11 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.992C>A	p.Ala331Glu	missense_variant	Exon 11 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250866

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135762

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

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

AF:

0.00

AC:

AN:

2712

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1428

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.:

Alfa

AF:

0.0000530

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:1

Mar 25, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 31, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with homocystinuria who also harbors a frameshift variant in the CBS gene (Dawson et al., 1997; Gaustadnes et al., 2002); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 212857; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect on protein function (Mayfield et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12124992, 12686134, 22267502, 9156316, 31301157) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Jul 23, 2024

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 glutamic acid, which is acidic and polar, at codon 331 of the CBS protein (p.Ala331Glu). This variant is present in population databases (rs777919630, gnomAD 0.0009%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9156316; Invitae). ClinVar contains an entry for this variant (Variation ID: 212857). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 9156316, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Oct 04, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.992C>A (p.Ala331Glu) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain 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 4e-06 in 250866 control chromosomes. c.992C>A has been reported in the literature in one individual affected with Homocystinuria in the compound heterozygous state (Dawson_1996, Gaustadnes_2002). Additionally, the variant has been reported to reduce CBS activity to less than 1% of wild-type, and was shown to be non-functional in a yeast-based assay (Dawson_1996, Mayfield_2012). 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 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

0.86

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;D;D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;.;.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;H;H;H

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.88

P;P;P;P

Vest4

0.93

MutPred

0.95

Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);

MVP

0.89

MPC

0.98

ClinPred

0.99

GERP RS

5.2

Varity_R

0.83

gMVP

0.97

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