rs149119723
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000071.3(CBS):c.785C>T(p.Thr262Met) variant causes a missense change involving the alteration of a conserved nucleotide. 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. T262A) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 3)
Exomes 𝑓: 0.000038 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 missense
NM_000071.3 missense
Scores
14
2
2
Clinical Significance
Conservation
PhyloP100: 8.70
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 hotspot region, there are 4 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 chr21-43063944-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1711543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
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Variant 21-43063943-G-A is Pathogenic according to our data. Variant chr21-43063943-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43063943-G-A is described in Lovd as [Pathogenic]. Variant chr21-43063943-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.785C>T | p.Thr262Met | missense_variant | 9/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.785C>T | p.Thr262Met | missense_variant | 9/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 9454Hom.: 0 Cov.: 3 FAILED QC
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GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249602Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135134
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 9454Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0AN XY: 4256
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2023 | Observed with a pathogenic variant in patients with homocystinuria in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in these cases (Gallagher et al., 1998; Yap et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that the p.(T262M) variant severely affects cystathionine beta-synthase enzyme activity (Kim et al., 1997; Singh et al., 2007; Mayfield et al., 2012); This variant is associated with the following publications: (PMID: 17540596, 23974653, 25087612, 22267502, 14722927, 20066033, 18849566, 28835823, 9361025, 10338090, 33057012, 9889017, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 25, 2023 | PP3, PM2_supporting, PM3_strong, PS3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | CBS: PM3:Strong, PM2, PM5, PP3, PP4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 21, 2014 | - - |
Classic homocystinuria Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 21, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 02, 2021 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 262 of the CBS protein (p.Thr262Met). This variant is present in population databases (rs149119723, gnomAD 0.01%). This missense change has been observed in individual(s) with very elevated homocysteine, and signs and symptoms highly specific for homocystinuria (PMID: 9361025). ClinVar contains an entry for this variant (Variation ID: 198988). 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: 9361025, 22267502). For these reasons, this variant has been classified as Pathogenic. - |
Homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2020 | Variant summary: CBS c.785C>T (p.Thr262Met) 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 2.8e-05 in 249602 control chromosomes (gnomAD and publication data). c.785C>T has been reported in the literature in multiple individuals affected with Homocystinuria, including one homozygote (Kim_1997, Kraus_1999, Al-Sadeq DW_2020). These data indicate that the variant is very likely to be associated with disease. In vitro study reports this variant has an impact on protein function and results in <10% of normal CBS activity in yeast. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
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
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MVP
MPC
1.1
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