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NM_000071.3(CBS):c.502G>A (p.Val168Met)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Sep 29, 2021)
Last evaluated:
May 19, 2021
Accession:
VCV000000127.6
Variation ID:
127
Description:
single nucleotide variant
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NM_000071.3(CBS):c.502G>A (p.Val168Met)

Allele ID
15166
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
21q22.3
Genomic location
21: 43065645 (GRCh38) GRCh38 UCSC
21: 44485755 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P35520:p.Val168Met
NC_000021.8:g.44485755C>T
NC_000021.9:g.43065645C>T
... more HGVS
Protein change
V168M, V63M
Other names
p.V168M:GTG>ATG
Canonical SPDI
NC_000021.9:43065644:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00003
Links
ClinGen: CA113895
UniProtKB: P35520#VAR_002180
OMIM: 613381.0011
dbSNP: rs121964970
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Apr 27, 2017 RCV000458159.2
Uncertain significance 1 criteria provided, single submitter Aug 22, 2019 RCV000250042.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations May 19, 2021 RCV000179250.5
Pathogenic 1 no assertion criteria provided Dec 1, 2003 RCV000000150.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CBS - - GRCh38
GRCh37
708 789

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Aug 29, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000231470.5
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (2)
Other databases
http://www.egl-eurofins.com/emvc…
Likely pathogenic
(May 19, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000249683.15
Submitted: (Sep 29, 2021)
Evidence details
Comment:
Has been reported in individuals with B6-responsive homocystinuria (Kruger et al., 1995; Shan et al., 1998), as well as an individual with spontaneous coronary artery … (more)
Uncertain significance
(Dec 08, 2016)
criteria provided, single submitter
Method: clinical testing
Classic homocystinuria
Allele origin: germline
Invitae
Accession: SCV000543513.2
Submitted: (Mar 14, 2017)
Evidence details
Comment:
This sequence change replaces valine with methionine at codon 168 of the CBS protein (p.Val168Met). The valine residue is moderately conserved and there is a … (more)
Uncertain significance
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Classic homocystinuria
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001298058.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (6)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Uncertain significance
(Aug 22, 2019)
criteria provided, single submitter
Method: clinical testing
Cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000317362.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
The p.V168M pathogenic mutation (also known as c.502G>A), located in coding exon 4 of the CBS gene, results from a G to A substitution at … (more)
Pathogenic
(Dec 01, 2003)
no assertion criteria provided
Method: literature only
HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE
Allele origin: germline
OMIM
Accession: SCV000020293.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (2)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Prospective Cardiovascular Genetics Evaluation in Spontaneous Coronary Artery Dissection. Kaadan MI Circulation. Genomic and precision medicine 2018 PMID: 29650765
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: structure, function, regulation, and location of homocystinuria-causing mutations. Miles EW The Journal of biological chemistry 2004 PMID: 15087459
Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Kruger WD Human mutation 2003 PMID: 14635102
Mutations in the regulatory domain of cystathionine beta synthase can functionally suppress patient-derived mutations in cis. Shan X Human molecular genetics 2001 PMID: 11230183
Deletion of the regulatory domain in the pyridoxal phosphate-dependent heme protein cystathionine beta-synthase alleviates the defect observed in a catalytic site mutant. Kabil O The Journal of biological chemistry 1999 PMID: 10531322
A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene. Kruger WD Human molecular genetics 1995 PMID: 8528202
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS - - - -

Text-mined citations for rs121964970...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 24, 2021