ClinVar Genomic variation as it relates to human health
NM_000071.3(CBS):c.959T>C (p.Val320Ala)
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.959T>C (p.Val320Ala)
Variation ID: 371028 Accession: VCV000371028.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 43062391 (GRCh38) [ NCBI UCSC ] 21: 44482501 (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 Jan 7, 2017 Feb 28, 2024 Sep 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000071.3:c.959T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000062.1:p.Val320Ala missense NM_001178008.3:c.959T>C NP_001171479.1:p.Val320Ala missense NM_001178009.3:c.959T>C NP_001171480.1:p.Val320Ala missense NM_001320298.2:c.959T>C NP_001307227.1:p.Val320Ala missense NM_001321072.1:c.644T>C NP_001308001.1:p.Val215Ala missense NC_000021.9:g.43062391A>G NC_000021.8:g.44482501A>G NG_008938.1:g.18540T>C LRG_777:g.18540T>C LRG_777t1:c.959T>C LRG_777p1:p.Val320Ala - Protein change
- V320A, V215A
- Other names
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- Canonical SPDI
- NC_000021.9:43062390:A: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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
Help
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 |
1252 | 1344 |
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
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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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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000410016.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2021 | RCV000780081.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2018 | RCV001000797.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 23, 2023 | RCV001861384.3 |
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
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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
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
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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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Pathogenic
(Oct 01, 2018)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001157857.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The CBS c.959T>C; p.Val320Ala variant (rs781567152) is reported in the literature in multiple individuals affected with homocystinuria in both the homozygous state and in individuals … (more)
The CBS c.959T>C; p.Val320Ala variant (rs781567152) is reported in the literature in multiple individuals affected with homocystinuria in both the homozygous state and in individuals with a second pathogenic variant (Kim 1997, Kruger 2003). This variant is reported in ClinVar (Variation ID: 371028), and it is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant at this codon (p.Val320Gly) has been reported in an individual with homocystinuria and is considered pathogenic (Lu 2012). The valine at codon 320 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Val320Ala variant is deleterious. Consistent with these predictions, functional analyses demonstrate that the p.Val320Ala variant exhibits significantly lower enzymatic activity than wildtype protein (Kruger 2003, Singh 2010) and fails to rescue yeast growth on media lacking a source of cysteine (Kim 1997, Mayfield 2012). Based on available information, this variant is considered to be pathogenic. References: Kim CE et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997 Dec;6(13):2213-21. Kruger WD et al. Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutat. 2003 Dec;22(6):434-41. Lu YH et al. Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao. Mol Genet Metab. 2012 Apr;105(4):590-5. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23. Singh LR et al. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet. 2010 Jan;6(1):e1000807. (less)
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Pathogenic
(Sep 27, 2021)
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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: SCV000917107.2
First in ClinVar: Jun 02, 2019 Last updated: Oct 30, 2021 |
Comment:
Variant summary: CBS c.959T>C (p.Val320Ala) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain of the encoded protein sequence. Five … (more)
Variant summary: CBS c.959T>C (p.Val320Ala) 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 1.6e-05 in 245462 control chromosomes (gnomAD and publication). c.959T>C has been reported in the literature in individuals affected with Homocystinuria (Guttormsen_2001, Kruger_2003). These data indicate that the variant is likely to be associated with disease. Multiple publications have assessed the variant for functional implications, which showed that the most pronounced variant effect results in <10% of normal activity (Kim_1997, Kruger_2003, Singh_2010, Mayfield_2012). Two 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jun 10, 2016)
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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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Counsyl
Accession: SCV000486482.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Sep 24, 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: SCV004213867.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Feb 23, 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: SCV002156643.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This missense change has been observed in individual(s) with CBS-related conditions (PMID: 9361025, 14635102). In at least one individual the data is consistent with being … (more)
This missense change has been observed in individual(s) with CBS-related conditions (PMID: 9361025, 14635102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CBS function (PMID: 9361025, 14635102). 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. ClinVar contains an entry for this variant (Variation ID: 371028). This variant is present in population databases (rs781567152, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 320 of the CBS protein (p.Val320Ala). (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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Surrogate genetics and metabolic profiling for characterization of human disease alleles. | Mayfield JA | Genetics | 2012 | PMID: 22267502 |
Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. | Singh LR | PLoS genetics | 2010 | PMID: 20066033 |
Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. | Kruger WD | Human mutation | 2003 | PMID: 14635102 |
Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype. | Guttormsen AB | American journal of medical genetics | 2001 | PMID: 11343305 |
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 |
Text-mined citations for rs781567152 ...
HelpRecord last updated Mar 05, 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.