ClinVar Genomic variation as it relates to human health
NM_000071.3(CBS):c.1224-2A>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
- Identifiers
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NM_000071.3(CBS):c.1224-2A>C
Variation ID: 128 Accession: VCV000000128.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 43058970 (GRCh38) [ NCBI UCSC ] 21: 44479080 (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 Apr 4, 2013 Apr 15, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000071.3:c.1224-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001178008.3:c.1224-2A>C splice acceptor NM_001178009.3:c.1224-2A>C splice acceptor NM_001320298.2:c.1224-2A>C splice acceptor NM_001321072.1:c.909-2A>C splice acceptor NC_000021.9:g.43058970T>G NC_000021.8:g.44479080T>G NG_008938.1:g.21961A>C LRG_777:g.21961A>C LRG_777t1:c.1224-2A>C - Protein change
- Other names
- IVS11AS, A-C, -2
- Canonical SPDI
- NC_000021.9:43058969:T:G
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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
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00015
- Comment on variant
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 |
1258 | 1350 |
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
Help
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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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1992 | RCV000000151.3 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2023 | RCV000174658.28 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV000198380.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 27, 2017 | RCV000590542.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV002227960.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2020 | RCV002354142.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV003944786.1 |
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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Pathogenic
(Mar 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Homocystinuria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695302.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The CBS c.1224-2A>C variant (alternatively also known as IVS11-2A>C) involves the alteration of a highly conserved intronic nucleotide in the canonical splice acceptor … (more)
Variant summary: The CBS c.1224-2A>C variant (alternatively also known as IVS11-2A>C) involves the alteration of a highly conserved intronic nucleotide in the canonical splice acceptor site in intron 13, and is expected to cause aberrant gene splicing. 5/5 splice prediction tools also predict abrogation of the splice acceptor site. Consistent to these predictions, this variant is shown to cause exon skipping resulting in an in-frame deletion of exon 12 (amino acids W408 to G453) (Kozick_1992); exon 12 is involved in encoding the CBS domain of the protein (InterPro). In addition, expression of this variant in bacterial (E. coli) system shows that this variant not only leads to abrogation of catalytic activity, but also non-responsiveness to chaperones used to treat the CBS deficiency (Orendac _2004, Kopecka_2011). This variant was found in 7/45474 control chromosomes from ExAC at a frequency of 0.0001539, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in several patients with CBS deficiency in homozygous as well as compound heterozygous with other pathogenic or potentially pathogenic variants including evidence of cosegregation with disease. It is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles with evidence of founder effect (Linnebank_2004). Available patient and functional data indicate that this variant is likely a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Classic homocystinuria
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914972.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Comment:
The CBS c.1224-2A>C variant, which occurs in a canonical splice acceptor site, has been reported in seven studies and is found in a total of … (more)
The CBS c.1224-2A>C variant, which occurs in a canonical splice acceptor site, has been reported in seven studies and is found in a total of 33 individuals with homocystinuria, including three homozygotes, 28 compound heterozygotes, and two heterozygotes (Kozich et al. 1992; Janosik et al. 2001; Orendae et al. 2004; Linnebank et al. 2004; Magner et al. 2011; Karaca et al. 2014; Alcaide et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Exome Aggregation Consortium. The c.1224-2A>C variant was found to cause an in-frame deletion of exon 12 and result in an inactive protein (Kozich et al. 1992). Functional studies in E. coli confirmed that the c.1224-2A>C variant results in an inactive enzyme (Janosik et al. 2001; Orendae et al. 2004), and CBS activity in cultured skin fibroblasts from probands carrying this variant was significantly reduced compared to wild type (Janosik et al. 2001). Based on the collective evidence and the potential impact of splice acceptor variants, the c.1224-2A>C variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Nov 09, 2021)
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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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Myriad Genetics, Inc.
Accession: SCV001194127.4
First in ClinVar: Apr 06, 2020 Last updated: Dec 24, 2022 |
Comment:
NM_000071.2(CBS):c.1224-2A>C is a canonical splice variant classified as pathogenic in the context of homocystinuria, CBS-related. c.1224-2A>C has been observed in cases with relevant disease (PMID: … (more)
NM_000071.2(CBS):c.1224-2A>C is a canonical splice variant classified as pathogenic in the context of homocystinuria, CBS-related. c.1224-2A>C has been observed in cases with relevant disease (PMID: 15365998). Functional assessments of this variant are available in the literature (PMID: 20506325, 20490928). c.1224-2A>C has been observed in population frequency databases (gnomAD: ASJ 0.14%). In summary, NM_000071.2(CBS):c.1224-2A>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Aug 25, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893551.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 11, 2023)
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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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Baylor Genetics
Accession: SCV004213857.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 19, 2023)
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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: SCV000831766.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 13 of the CBS gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects an acceptor splice site in intron 13 of the CBS gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs375846341, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with homocystinuria (PMID: 1301198, 11359213, 15146473, 15365998, 20567906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS11-2A>C or p.W409_G453del. ClinVar contains an entry for this variant (Variation ID: 128). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 1301198, 20490928, 20506325). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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CBS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004765662.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CBS c.1224-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the … (more)
The CBS c.1224-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state or with a second CBS variant in individuals with homocystinuria, and has been shown to cause skipping of exon 14 (for example, see Kozich et al 1992. PubMed ID: 1301198; Linnebank et al. 2004. PubMed ID: 15365998; Kopecká et al 2010. PubMed ID: 20490928). In at least one individual, this variant was shown by family segregation studies to be on the opposite allele as a known pathogenic variant in CBS (Kozich et al 1992. PubMed ID: 1301198). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice acceptor site in CBS are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 02, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000225996.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Classic homocystinuria
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367386.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Classic homocystinuria
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573357.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). This variant on the canonical splice site … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). This variant on the canonical splice site is predicted to alter splicing, resulting in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000128). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Ectopia lentis (present) , Iridodonesis (present) , High myopia (present) , Shortened PR interval (present) , Delayed speech and language development (present) , Chronic bronchitis … (more)
Ectopia lentis (present) , Iridodonesis (present) , High myopia (present) , Shortened PR interval (present) , Delayed speech and language development (present) , Chronic bronchitis (present) (less)
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Pathogenic
(Nov 24, 2020)
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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: SCV002654814.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.1224-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 12 in the CBS gene. This alteration … (more)
The c.1224-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 12 in the CBS gene. This alteration has been reported with p.I278T in a subject with homocystinuria (Kozich V et al. Hum Mutat, 1992;1:113-23). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 07, 2023)
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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: SCV000249712.14
First in ClinVar: Oct 11, 2015 Last updated: Jul 22, 2023 |
Comment:
Segregates with disease in affected individuals from a single family in published literature (Orendae et al., 2004); Published functional studies demonstrate decreases enzyme activity (Kozich … (more)
Segregates with disease in affected individuals from a single family in published literature (Orendae et al., 2004); Published functional studies demonstrate decreases enzyme activity (Kozich et al., 1992; Kopeck et al., 2011; Alcaide et al., 2015); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24211323, 21030686, 1301198, 27059523, 20567906, 25525159, 15365998, 20490928, 20506325, 15146473, 11359213, 32232970, 25218699) (less)
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Pathogenic
(Jun 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Classic homocystinuria
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238581.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033912.5
First in ClinVar: Sep 16, 2023 Last updated: Apr 15, 2024 |
Comment:
CBS: PVS1:Strong, PM2, PM3, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 1992)
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no assertion criteria provided
Method: literature only
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HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020294.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a mildly affected patient of Ashkenazi Jewish origin with pyridoxine-responsive homocystinuria (236200), Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation … (more)
In a mildly affected patient of Ashkenazi Jewish origin with pyridoxine-responsive homocystinuria (236200), Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation (613381.0004) and a paternal A-to-C transversion in the intron 11 splice acceptor. The latter mutation led to an in-frame deletion of exon 12. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Classic homocystinuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Child Health and Human Development Program, Research Institute of the McGill University Health Center
Accession: SCV001424582.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
The IVS11-2 A>C (also c.1224-2A>C) was identified in two patients of Eastern European origin in compound heterozygote with c.833C>T (I278T) in one of the patients … (more)
The IVS11-2 A>C (also c.1224-2A>C) was identified in two patients of Eastern European origin in compound heterozygote with c.833C>T (I278T) in one of the patients and c.430G>C (E144Q) in the other. Clinical characteristics in both patients included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6. (less)
Number of individuals with the variant: 2
Ethnicity/Population group: Eastern European
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Pathogenic
(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: SCV001461064.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. | Alcaide P | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25218699 |
High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands. | Karaca M | Gene | 2014 | PMID: 24211323 |
Vascular presentation of cystathionine beta-synthase deficiency in adulthood. | Magner M | Journal of inherited metabolic disease | 2011 | PMID: 20567906 |
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 |
The cystathionine beta-synthase (CBS) mutation c.1224-2A>C in Central Europe: Vitamin B6 nonresponsiveness and a common ancestral haplotype. | Linnebank M | Human mutation | 2004 | PMID: 15365998 |
Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria. | Orendáè M | Human mutation | 2004 | PMID: 15146473 |
Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. | Janosík M | American journal of human genetics | 2001 | PMID: 11359213 |
Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency. | Kozich V | Human mutation | 1992 | PMID: 1301198 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS | - | - | - | - |
Text-mined citations for rs375846341 ...
HelpRecord last updated Apr 15, 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.
NCBI staff reviewed the sequence information reported in PubMed 1301198 Fig. 7B to determine the location of this allele on the current reference sequence