21-43062311-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000071.3(CBS):c.1039G>A(p.Gly347Ser) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 0)
Consequence
CBS
NM_000071.3 missense, splice_region
NM_000071.3 missense, splice_region
Scores
13
5
1
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 6.85
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 12 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 21-43062311-C-T is Pathogenic according to our data. Variant chr21-43062311-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062311-C-T is described in Lovd as [Pathogenic]. Variant chr21-43062311-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
0
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
GnomAD4 genome
GnomAD4 genome
Cov.:
0
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Child Health and Human Development Program, Research Institute of the McGill University Health Center | - | The c.1039G>A (G347S) was identified in a patients of Eastern European origin in compound heterozygote with c.526G>A (E176K). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 22, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that p.(G347S) is associated with very low levels of residual cystathionine beta-synthase enzyme activity compared to wild-type (PMID: 12124992); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 22267502, 16205833, 21517828, 24211323, 19914636, 16307898, 19370759, 30202406, 12124992) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 05, 2023 | PP3, PM2_supporting, PM3, PS3, PS4_moderate - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2024 | The p.G347S pathogenic mutation (also known as c.1039G>A), located in coding exon 9 of the CBS gene, results from a G to A substitution at nucleotide position 1039. The glycine at codon 347 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 9 and may have some effect on normal mRNA splicing. This variant has been identified in the homozygous state and/or in conjunction with other CBS variant(s) in individual(s) with features consistent with homocystinuria (Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Lee SJ et al. J. Hum. Genet., 2005 Oct;50:648-54; Katsushima F et al. Mol. Genet. Metab., 2006 Apr;87:323-8; Zschocke J et al. Hum. Mutat., 2009 Jun;30:1021-2; Karaca M et al. Gene, 2014 Jan;534:197-203; Yubero D et al. PLoS ONE, 2016 May;11:e0156359; Alfares AA. Int J Health Sci (Qassim). 2018;12:35-43). In addition, this variant has been reported to result in absence of, or significantly reduced, enzyme activity in various expression systems, and was reported as non-functional in a yeast growth assay (Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Lee SJ et al. J. Hum. Genet., 2005 Oct;50:648-54). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 347 of the CBS protein (p.Gly347Ser). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs771298943, gnomAD 0.007%). This missense change has been observed in individuals with homocystinuria (PMID: 12124992, 16205833, 16307898, 19370759, 24211323). ClinVar contains an entry for this variant (Variation ID: 188801). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 | Dec 14, 2018 | Variant summary: CBS c.1039G>A (p.Gly347Ser) 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 3.2e-05 in 30882 control chromosomes. c.1039G>A has been reported in the literature in multiple individuals affected with Homocystinuria (Gaustadnes_2002, Lee_2005, Katsushima_2006, Karaca_2014, Yubero_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Lee_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and 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
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at