rs398123151
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.1006C>T(p.Arg336Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) 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
15
3
1
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]
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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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-43062343-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 21-43062344-G-A is Pathogenic according to our data. Variant chr21-43062344-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062344-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.1006C>T | p.Arg336Cys | missense_variant | 11/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.1006C>T | p.Arg336Cys | missense_variant | 11/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 0
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250690Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135676
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 2302Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 1212
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:7Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 21, 2020 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 25, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 26, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2021 | Reported to be a founder mutation in the Qatari population, affecting approximately 1 in 1,8000 births (Gan-Schreier et al., 2010; El Bashir et al., 2015); Functional studies showed reduced activity of R336C in mammalian (Ismail et al., 2019) and E-coli expression systems (Urreizti et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31240737, 26582918, 30408270, 12815602, 19914636, 27629047, 25218699, 25712383, 7762555, 23685761, 26464485, 10408774, 21517828, 16786517, 21240075, 7967489, 21062078, 16429402, 12124992, 16205833, 19370759, 20455263, 30968424, 31130284) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 336 of the CBS protein (p.Arg336Cys). This variant is present in population databases (rs398123151, gnomAD 0.004%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 16205833, 21517828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92423). 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. Experimental studies have shown that this missense change affects CBS function (PMID: 10408774, 16205833, 16429402, 26464485). This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9870207, 23974653, 25218699). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
CBS-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | The CBS c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Cys. This variant has previously been reported in the homozygous state or with a second causative CBS variant in numerous patients with homocystinuria (Zaidi et al. 2011. PubMed ID: 21517828; Lee et al. 2005. PubMed ID: 16205833; Alcaide et al. 2014. PubMed ID: 25218699; Gaustadnes et al. 2002. PubMed ID: 12124992; de Franchis et al. 1999. PubMed ID: 10408774; Urreizti et al. 2003. PubMed ID: 12815602). This is the most commonly reported causative variant in the CBS gene in individuals in Qatar (El-Said et al. 2006. PubMed ID: 16786517; Zschocke et al. 2009. PubMed ID: 19370759). A different substitution affecting the same amino acid (p.Arg336His) was also reported in patients with homocystinuria (Coude et al.1998. PubMed ID: 9870207; Kumar et al. 2022. PubMed ID: 36065636). In vitro functional studies have shown that both p.Arg336Cys and p.Arg336His substitutions lead to decreased amount of protein and enzyme activity (Lee et al. 2005. PubMed ID: 16205833; Urreizti et al. 2006. PubMed ID: 16429402; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2020 | Variant summary: CBS c.1006C>T (p.Arg336Cys) 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 2e-05 in 250690 control chromosomes (gnomAD). The variant, c.1006C>T, has been reported in the literature in several homozygous and compound heterozygous individuals affected with Homocystinuria (e.g. deFranchis_1999, Urreizti_2003, El-Said_2006, Zaidi_2012); in addition, the variant was identified as a founder mutation in Qatar (El-Said_2006). These data indicate that the variant is very likely to be associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzymatic activity (see e.g. deFranchis_1999, Urreizti_2003, Urreizti_2006, Mendes_2015), in addition, recently a transgenic mouse model was also developed with mice showing marked elevation in serum homocysteine (Gupta_2019). Four 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. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
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
LIST_S2
Uncertain
.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
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
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at