ClinVar Genomic variation as it relates to human health
NM_000071.3(CBS):c.[233C>G;306G>C]
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
NM_000071.3(CBS):c.[233C>G;306G>C]
- Other names
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- Functional consequence
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- Links
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CBS | - | - |
GRCh38 GRCh37 |
1249 | 1339 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Mar 15, 2023 | RCV003226626.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Mar 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922490.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: CBS c.[233C>G;306G>C] (p.[Pro78Arg;Lys102Asn]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant was absent in 251330 control chromosomes … (more)
Variant summary: CBS c.[233C>G;306G>C] (p.[Pro78Arg;Lys102Asn]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant was absent in 251330 control chromosomes although each individual component is present at a frequency of 4e-06 in 251330 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.[233C>G;306G>C] has been reported in the literature as a complex allele in a biparentally confirmed compound heterozygous genotype with c.715G>A (p.E239K) (not reported in ClinVar) in trans in two affected siblings with features of Homocystinuria and their unaffected brother (deFranchis_1994). Since the penetrance of Homocystinuria due to this variant appears to be lower than expected, no conclusions can be drawn from these data. Therefore, this report does not provide unequivocal conclusions about association of the variant with Homocystinuria. At least two publications report conflicting experimental evidence evaluating an impact on protein function (deFranchis_1994, Sen_2007). The most pronounced variant effect results in 0% of normal CBS activity in one study while reporting activity levels comparable to the wild-type with unresponsiveness to the allosteric activator AdoMet in the other (Sen_2007). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the complex allele variant was classified as uncertain significance. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. | Melenovská P | Journal of inherited metabolic disease | 2015 | PMID: 25331909 |
Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. | Melenovská P | Journal of inherited metabolic disease | 2015 | PMID: 25331909 |
Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. | Melenovská P | Journal of inherited metabolic disease | 2015 | PMID: 25331909 |
Human cystathionine β-synthase (CBS) contains two classes of binding sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM. | Pey AL | The Biochemical journal | 2013 | PMID: 22985361 |
Conformational properties of nine purified cystathionine β-synthase mutants. | Hnízda A | Biochemistry | 2012 | PMID: 22612060 |
Surrogate genetics and metabolic profiling for characterization of human disease alleles. | Mayfield JA | Genetics | 2012 | PMID: 22267502 |
Surrogate genetics and metabolic profiling for characterization of human disease alleles. | Mayfield JA | Genetics | 2012 | PMID: 22267502 |
Surrogate genetics and metabolic profiling for characterization of human disease alleles. | Mayfield JA | Genetics | 2012 | PMID: 22267502 |
Restoring assembly and activity of cystathionine β-synthase mutants by ligands and chemical chaperones. | Kopecká J | Journal of inherited metabolic disease | 2011 | PMID: 20490928 |
Restoring assembly and activity of cystathionine β-synthase mutants by ligands and chemical chaperones. | Kopecká J | Journal of inherited metabolic disease | 2011 | PMID: 20490928 |
Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. | Kozich V | Human mutation | 2010 | PMID: 20506325 |
Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. | Kozich V | Human mutation | 2010 | PMID: 20506325 |
Rescue of cystathionine beta-synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. | Majtan T | The Journal of biological chemistry | 2010 | PMID: 20308073 |
A pathogenic linked mutation in the catalytic core of human cystathionine beta-synthase disrupts allosteric regulation and allows kinetic characterization of a full-length dimer. | Sen S | Biochemistry | 2007 | PMID: 17352495 |
A pathogenic linked mutation in the catalytic core of human cystathionine beta-synthase disrupts allosteric regulation and allows kinetic characterization of a full-length dimer. | Sen S | Biochemistry | 2007 | PMID: 17352495 |
A pathogenic linked mutation in the catalytic core of human cystathionine beta-synthase disrupts allosteric regulation and allows kinetic characterization of a full-length dimer. | Sen S | Biochemistry | 2007 | PMID: 17352495 |
Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase. | Yamanishi M | Journal of inorganic biochemistry | 2006 | PMID: 17069888 |
Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase. | Yamanishi M | Journal of inorganic biochemistry | 2006 | PMID: 17069888 |
Structural insights into mutations of cystathionine beta-synthase. | Meier M | Biochimica et biophysica acta | 2003 | PMID: 12686134 |
Structural insights into mutations of cystathionine beta-synthase. | Meier M | Biochimica et biophysica acta | 2003 | PMID: 12686134 |
Cystathionine beta-synthase mutations in homocystinuria. | Kraus JP | Human mutation | 1999 | PMID: 10338090 |
Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system. | de Franchis R | Human molecular genetics | 1994 | PMID: 7981678 |
Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system. | de Franchis R | Human molecular genetics | 1994 | PMID: 7981678 |
Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system. | de Franchis R | Human molecular genetics | 1994 | PMID: 7981678 |
Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. | Kraus JP | Journal of inherited metabolic disease | 1994 | PMID: 7967489 |
Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. | Kraus JP | Journal of inherited metabolic disease | 1994 | PMID: 7967489 |
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Text-mined citations for this variant ...
HelpRecord last updated Jan 26, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.