ClinVar Genomic variation as it relates to human health
NM_000071.2(CBS):c.832_833insCTGGGGTGGATCATCCAGGTGGGGCTTTTGCTGGGCTTGAGCCCTGAAGCCGCGCCCTCTGCAGATCA
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
- Identifiers
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NM_000071.2(CBS):c.832_833insCTGGGGTGGATCATCCAGGTGGGGCTTTTGCTGGGCTTGAGCCCTGAAGCCGCGCCCTCTGCAGATCA
Variation ID: 226482 Accession: VCV000226482.31
- Type and length
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Insertion, 68 bp
- Location
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Cytogenetic: 21q22.3 21: 43063074-43063075 (GRCh38) [ NCBI UCSC ] 21: 44483184-44483185 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 May 1, 2024 Feb 1, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
1260 | 1352 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
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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Benign (1) |
criteria provided, single submitter
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Jun 9, 2015 | RCV000222887.12 | |
Likely benign (2) |
criteria provided, single submitter
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May 28, 2019 | RCV000990351.13 | |
Benign (1) |
no assertion criteria provided
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Nov 1, 1998 | RCV002225098.9 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV002229201.13 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV001573597.21 | |
Benign (1) |
criteria provided, single submitter
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Nov 29, 2021 | RCV004020589.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
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
Help
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
Help
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
Help
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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Benign
(Jun 09, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000268837.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
c.832_833ins68 in intron 9 of CBS: This variant is not expected to have clinical significance because it has been identified in 8% (632/8000) of African … (more)
c.832_833ins68 in intron 9 of CBS: This variant is not expected to have clinical significance because it has been identified in 8% (632/8000) of African chromos omes, 3.5% (551/15982) of South Asian chromosomes, and 2.1% (1306/61690) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org). (less)
Number of individuals with the variant: 2
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141299.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(Jul 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001905133.1
First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 10363126, 22002135, 17072863, 14722927, 7762555, 20601281, 8940271, 9813456, 19906435, 8940285, 11204591)
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000555943.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Benign
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002058026.6
First in ClinVar: Jan 15, 2022 Last updated: Feb 20, 2024 |
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Benign
(Nov 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003699441.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(Nov 01, 1998)
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no assertion criteria provided
Method: literature only
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CYSTATHIONINE BETA-SYNTHETASE POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020299.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
Sebastio et al. (1995) identified a 68-bp insertion in exon 8 of the CBS gene in a patient with homocystinuria and predicted that it would … (more)
Sebastio et al. (1995) identified a 68-bp insertion in exon 8 of the CBS gene in a patient with homocystinuria and predicted that it would introduce a premature termination codon and result in a nonfunctional CBS enzyme. However, Tsai et al. (1996) found that this mutation is highly prevalent. In a case-control study involving patients with premature coronary artery disease, they identified the mutation in heterozygosity in 11.7% of controls and in slightly higher prevalence in the patients, although the difference did not reach statistical significance. In all cases, the insertion was present in cis with the 833T-C (I278T; 613381.0004) mutation. Tsai et al. (1996) suggested that the insertion created an alternate splicing site that eliminated not only the inserted intronic sequences, but also the 833T-C mutation associated with this insertion. The net result was the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. Sperandeo et al. (1996) also identified the 68-bp insertion as a benign polymorphism in an Italian cohort. Kim et al. (1997) studied the mutations in 10 Norwegian CBS-deficient families and identified 18 of the 20 mutant alleles. In 9 of the 20 CBS alleles (45%), they found the 68-bp duplication allele. This frequency was much higher than the 6% reported by Tsai et al. (1996) in a study population from the upper midwest of the US. In unaffected Norwegian chromosomes, Kim et al. (1997) found the frequency of the duplication to be approximately 5.5% (2 in 36). Franco et al. (1998), who referred to the 68-bp insertion in the coding region of exon 8 of the CBS gene as 844ins68, investigated its prevalence in 405 persons belonging to 4 different ethnic groups. The insertion was found in heterozygous state in 14 of 104 whites (13.5%), was absent among Asians, and was found in only 1 of 220 Amerindian chromosomes analyzed, whereas a much higher prevalence was observed among blacks (37.7% of heterozygotes and 4% of mutant homozygotes). In all carriers of the insertion, the 833T-C CBS mutation cosegregated in cis with 844ins68. The finding of the double mutant among blacks and Caucasians suggested that it antedated the divergence between Africans and non-Africans, and provided evidence for a partly or completely neutralizing effect conferred by the 68-bp insertion, since it allows the skipping of the 833T-C mutation. (less)
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Benign
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Homocystinuria due to cystathionine beta-synthase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462117.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799727.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919850.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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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Prevalence of cystathionine beta synthase gene mutation 852Ins68 as a possible risk for neural tube defects in eastern India. | Saxena AK | Genetics and molecular research : GMR | 2011 | PMID: 22002135 |
G runs in cystathionine beta-synthase c.833C/c.844_845ins68 mRNA are splicing silencers of pathogenic 3' splice sites. | Romano M | Biochimica et biophysica acta | 2010 | PMID: 20601281 |
The 844ins68 polymorphism of the cystathionine beta-synthase gene is associated with schizophrenia. | Golimbet V | Psychiatry research | 2009 | PMID: 19906435 |
Gene-environment and gene-gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men. | Dekou V | Thrombosis and haemostasis | 2001 | PMID: 11204591 |
Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine. The Ears II Group. European Atherosclerosis Research Study. | De Stefano V | Annals of human genetics | 1998 | PMID: 10363126 |
Heterogeneous ethnic distribution of the 844ins68 in the cystathionine beta-synthase gene. | Franco RF | Human heredity | 1998 | PMID: 9813456 |
Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. | Kim CE | Human molecular genetics | 1997 | PMID: 9361025 |
A 68-bp insertion found in a homocystinuric patient is a common variant and is skipped by alternative splicing of the cystathionine beta-synthase mRNA. | Sperandeo MP | American journal of human genetics | 1996 | PMID: 8940285 |
High prevalence of a mutation in the cystathionine beta-synthase gene. | Tsai MY | American journal of human genetics | 1996 | PMID: 8940271 |
The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. | Sebastio G | American journal of human genetics | 1995 | PMID: 7762555 |
Sebastio, G. Personal Communication. 1997. Padua, Italy | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated May 01, 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.