rs786204495
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_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 Likely pathogenic.
Frequency
Genomes: not found (cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 missense
NM_000071.3 missense
Scores
8
9
1
Clinical Significance
Conservation
PhyloP100: 5.78
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000071.3
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr21-43060451-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.1136G>A | p.Arg379Gln | missense_variant | 12/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.1136G>A | p.Arg379Gln | missense_variant | 12/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
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GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249472Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135332
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 24284Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 13382
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
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GnomAD4 genome ? Cov.: 0
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
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 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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%). - |
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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;P;P;P
Vest4
MutPred
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
MPC
0.96
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at