21-43062358-G-T

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

9
7
3

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]

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
CBSNM_000071.3 linkc.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
CBSENST00000398165.8 linkc.992C>A p.Ala331Glu missense_variant Exon 11 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250866
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
0
AN:
2712
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
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.:
0
Alfa
AF:
0.0000530
Hom.:
0
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

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
D
BayesDel_noAF
Pathogenic
0.50
CADD
Uncertain
25
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
D
LIST_S2
Uncertain
0.93
.;.;.;D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
1.0
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.1
H;H;H;H
PrimateAI
Benign
0.39
T
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
D
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.

Other links and lift over

dbSNP: rs777919630; hg19: chr21-44482468; API