NM_000071.3(CBS):c.919G>A (p.Gly307Ser)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (17)
Pathogenic (17)
17 out of 22 submissions contributed to this classification
Help
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.
22
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000071.3(CBS):c.919G>A (p.Gly307Ser)
Variation ID: 117 Accession: VCV000000117.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 43062988 (GRCh38) [ NCBI UCSC ] 21: 44483098 (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 Jun 28, 2015 Jun 20, 2026 Jan 26, 2026 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000071.3:c.919G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000062.1:p.Gly307Ser missense NM_001178008.3:c.919G>A NP_001171479.1:p.Gly307Ser missense NM_001178009.3:c.919G>A NP_001171480.1:p.Gly307Ser missense NM_001320298.2:c.919G>A NP_001307227.1:p.Gly307Ser missense NM_001321072.1:c.604G>A NP_001308001.1:p.Gly202Ser missense NC_000021.9:g.43062988C>T NC_000021.8:g.44483098C>T NG_008938.1:g.17943G>A LRG_777:g.17943G>A LRG_777t1:c.919G>A LRG_777p1:p.Gly307Ser P35520:p.Gly307Ser - Protein change
- G307S, G202S
- Other names
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p.G307S:GGC>AGC
- Canonical SPDI
- NC_000021.9:43062987:C:T
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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.
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The Genome Aggregation Database (gnomAD), exomes 0.00016
The Genome Aggregation Database (gnomAD) 0.00025
Exome Aggregation Consortium (ExAC) 0.00016
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
1447 | 1546 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jan 28, 2003 | RCV000000137.13 | |
| Pathogenic (2) |
criteria provided, single submitter
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Jan 26, 2026 | RCV000000138.19 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2025 | RCV000078112.48 | |
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Dec 15, 2025 | RCV000173641.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 6, 2017 | RCV000366433.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2023 | RCV002313701.9 | |
|
CBS-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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May 17, 2024 | RCV003914786.2 |
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. |
Expand all rows
Collapse all rows
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria |
Illumina Laboratory Services, Illumina
Accession: SCV000436215.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
show
The CBS c.919G>A (p.Gly307Ser) variant is well described as a common pathogenic allele in individuals with homocystinuria of Celtic origin, accounting for 71% of disease associated alleles in Ireland, 21% in the UK and 8% in the US (Moat et al. 2004). The presence of a single allele almost always predicts non-responsiveness to pyroxidine therapy. The p.Gly307Ser variant has been reported in at least six studies in which it is found in a total of 44 individuals including 14 in a homozygous state (including two pairs of siblings), ten in a compound heterozygous state (four of whom were related), and 20 heterozygotes in whom a second allele has not yet been identified (Hu et al. 1993; Gallagher et al. 1995; Kim et al. 1997; Kelly et al. 2003; Moat et al. 2004; Stabler et al. 2013). The variant was also found in at least three unaffected heterozygous relatives. The variant was absent from 82 control chromosomes but is reported at a frequency of 0.00026 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies have demonstrated that the Gly307 residue is located in the catalytic site of the protein and results in the production of correctly assembled tetramers that are slightly unfolded with a shift towards unfolded intermediates. The catalytic activity of the p.Gly307Ser variant protein is completely abolished (Hu et al. 1993; Hnizda et al. 2012). Based on the collective evidence, the p.Gly307Ser 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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(May 08, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria
(Autosomal recessive inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711669.2
First in ClinVar: Apr 09, 2018 Last updated: Jul 06, 2020 |
Comment:
show
The p.Gly307Ser variant in CBS has been reported in at least 11 homozygous, 4 compound heterozygous and 15 heterozygous (where the second variant has not been reported) probands with homocystinuria and segregated with disease in 5 affected family members (Hu 1993, Dawson 1996, Stabler 2013, Gallagher 1995, Moat 2004). It was also reported in 1 heterozygous individual with homocystinuria and reversible cerebral white matter abnormalities who was also heterozygous for the MTHFR c.677C>T variant (Ismayilova 2019). This variant has been reported in ClinVar (ClinVar ID 117). In addition, in vitro functional studies provide evidence that the variant leads to impaired protein function (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012). This variant has also been identified in 41/129158 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_very_strong, PP1_strong, PS3_supporting. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial thoracic aortic aneurysm and aortic dissection |
Ambry Genetics
Accession: SCV000738476.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
show
The p.G307S pathogenic mutation (also known as c.919G>A), located in coding exon 8 of the CBS gene, results from a G to A substitution at nucleotide position 919. The glycine at codon 307 is replaced by serine, an amino acid with similar properties. This alteration was described to account for about 70% of disease alleles in Ireland (Gallagher PM et al. Hum. Mutat., 1995;6:177-80), 21% in UK and 8% in US (Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). This alteration has been reported in the homozygous state in multiple individuals with homocysteinuria, as well as in the heterozygous state in patients with an (un)identified second allele (Dawson PA et al. Aust N Z J Med, 1996 Apr;26:180-5; Gallagher PM et al. Hum. Mutat., 1995;6:177-80; Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). In addition, this alteration was reported to occur in the enzyme active site (Meier M et al. Biochim. Biophys. Acta, 2003 Apr;1647:206-13), and in vitro studies have consistently suggested that this change would abolish enzyme activity, probably by interfering with protein folding (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hnízda A et al. J. Inherit. Metab. Dis., 2012 May;35:469-77). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
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Pathogenic
(Mar 25, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria |
Revvity Omics, Revvity
Accession: SCV006312377.1
First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
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Pathogenic
(Jan 26, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543511.11
First in ClinVar: Jun 28, 2015 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CBS protein (p.Gly307Ser). This variant is present in population databases (rs121964962, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 117). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
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Pathogenic
(Sep 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821086.26
First in ClinVar: Jan 21, 2023 Last updated: Jun 20, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 4
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Pathogenic
(Apr 06, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695310.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
show
Variant summary: The CBS c.919G>A (p.Gly307Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/121292 control chromosomes at a frequency of 0.0001566, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in many affected individuals and functional study showed variant with <1% activity in comparison with WT (Kozich_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(Apr 04, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893554.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
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Pathogenic
(Nov 20, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000224773.6
First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 11
Zygosity: 1 Homozygote, 10 Single Heterozygotes
Sex: mixed
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Pathogenic
(Mar 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV007333016.1
First in ClinVar: Jan 24, 2026 Last updated: Jan 24, 2026 |
Comment:
show
The CBS c.919G>A; p.Gly307Ser variant (rs121964962, ClinVar Variation ID: 117) is reported in the literature in numerous individuals affected with homocystinuria often found homozygous or compound heterozygous (Dawson 1996, Hu 1993, Kelly 2003, Moat 2004, Stabler 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (41/129158 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show absent or near absent enzyme activity when compared to the wildtype (Hnizda 2012, Hu 1993, Mayfield 2012). Computational analyses predict that this variant is deleterious (REVEL: 0.946). Based on available information, this variant is considered to be pathogenic. References: Dawson PA et al. Variable hyperhomocysteinaemia phenotype in heterozygotes for the Gly307Ser mutation in cystathionine beta-synthase. Aust N Z J Med. 1996 Apr;26(2):180-5. PMID: 8744616. Hnizda A et al. Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Inherit Metab Dis. 2012 May;35(3):469-77. PMID: 22069143. Hu FL et al. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet. 1993 Nov;2(11):1857-60. PMID: 7506602. Kelly PJ et al. Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology. 2003 Jan 28;60(2):275-9. PMID: 12552044. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23Epub 2012 Jan 20. Erratum in: Genetics. 2012 Oct;192(2):759-60. PMID: 22267502. Moat SJ et al. The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat. 2004 Feb;23(2):206. PMID: 14722927. Stabler SP et al. Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 2013; 11:149-63. PMID: 23733603. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Dec 15, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Homocystinuria due to cystathionine beta-synthase deficiency |
Natera, Inc.
Accession: SCV001462113.2
First in ClinVar: Jan 02, 2021 Last updated: Apr 04, 2026 |
Comment:
show
The c.919G>A variant in CBS is a missense variant predicted to cause substitution of glycine to serine at amino acid 307. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 12124992). Additionally, this variant has been observed to segregate in affected family members (PMID: 12124992). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Nov 12, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria |
Myriad Genetics, Inc.
Accession: SCV001193980.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
show
NM_000071.2(CBS):c.919G>A(G307S) is classified as pathogenic in the context of CBS-related homocystinuria, and is associated with the B6-non-responsive form of this disease. Sources cited for classification include the following: PMID 9889017, 20506325, 7506602 and 22267502. Classification of NM_000071.2(CBS):c.919G>A(G307S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
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Pathogenic
(Nov 05, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000249696.14
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
show
Common pathogenic variant found on approximately 70% of alleles in patients of Celtic origin with homocystinuria due to cystathionine beta-synthase (CBS) deficiency and is usually associated with a more severe non-B6 responsive phenotype (Urreizti et al., 2006); Functional studies found that G307S is associated with significantly decreased CBS enzyme activity compared to wild-type (Hu et al. 1993; Kozich et al. 2010; Hnizda et al. 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 7581402, 14722927, 7564249, 17319270, 12552044, 8744616, 22267502, 23733603, 22069143, 7506602, 16479318, 30609409, 30187370, 12686134, 18280597, 12124992, 9361025, 25636110, 20506325) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Nov 05, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria
(Autosomal recessive inheritance)
|
Genetics and Molecular Pathology, SA Pathology
Accession: SCV004175579.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Mar 28, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria |
Baylor Genetics
Accession: SCV001163819.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
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Pathogenic
(Jan 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV007138769.1
First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
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Pathogenic
(Jun 20, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Classic homocystinuria
(Autosomal recessive inheritance)
|
First Genomix Gene Laboratory, Genetic Diagnostics Department
Accession: SCV007591683.1
First in ClinVar: May 03, 2026 Last updated: May 03, 2026 |
Comment:
show
As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition. (less)
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Number of individuals with the variant: 1
|
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Pathogenic
(May 17, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
CBS-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004727959.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
show
The CBS c.919G>A variant is predicted to result in the amino acid substitution p.Gly307Ser. This variant is one of the most commonly reported CBS variants causative for homocystinuria due to cystathionine beta-synthase deficiency (e.g., Gallagher et al. 1995. PubMed ID: 7581402; Kraus et al. 1999. PubMed ID: 10338090). In experimental studies, the p.Gly307Ser substitution has been shown to greatly impair CBS enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jan 28, 2003)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
HOMOCYSTINURIA, PYRIDOXINE-NONRESPONSIVE |
OMIM
Accession: SCV000020280.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
Homocystinuria In 2 unrelated patients with homocystinuria (236200), Gu et al. (1991) found a G-to-A transition in the CBS gene, resulting in a gly307-to-ser (G307S) … (more)
Homocystinuria In 2 unrelated patients with homocystinuria (236200), Gu et al. (1991) found a G-to-A transition in the CBS gene, resulting in a gly307-to-ser (G307S) substitution. Functional expression studies in E. coli showed a peptide of normal mobility that lacked CBS activity. Hu et al. (1993) found the G307S mutation in one allele of a patient of French/Scottish ancestry and in both alleles of a patient of Irish ancestry. Both parents of the second patient were heterozygotes for G307S. The mutant protein was apparently stable in expression studies in E. coli but lacked catalytic activity. Sequencing of exon 8 revealed the G307S mutation in 5 additional families. All had pyridoxine-nonresponsive homocystinuria. Hu et al. (1993) observed this mutation in 9 of 52 apparently unrelated alleles of varied ethnic backgrounds. All 9 were from patients with Celtic (Irish/English/Scottish/French) ancestry in either one or both parents. Indeed, the G307S mutation was detected in 9 of 18 Celtic alleles in their series. A second mutation found in exon 8 (I278T; 613381.0004) was associated with pyridoxine responsiveness. Gallagher et al. (1995) analyzed 17 Irish unrelated persons with homocystinuria for the G307S mutation. Homozygosity for the mutation was found in 8 of the 17. A further 8 patients were compound heterozygotes, with the G307S mutation present on 1 allele. Of the 34 alleles, 24 (71%) were G307S. Screening of newborns for homocystinuria has been routine in Ireland since 1971. Newly diagnosed infants are also assessed for responsiveness to pyridoxine; all patients analyzed by Gallagher et al. (1995) were nonresponsive. Kim et al. (1997) found a different distribution of CBS alleles in Norwegian cystinurics. The G307S mutation, which was found in 71% of mutant alleles in Ireland, accounted for only 20% in the Norwegian group and in Italian patients was not observed at all (Sperandeo et al., 1995). Hyperhomocysteinemia, Thrombotic, CBS-related In a patient with early-onset stroke and hyperhomocysteinemia without other manifestations of classic homocystinuria (see 236200), Kelly et al. (2003) identified a heterozygous G307S mutation. The patient was an 18-year-old Irish man with mitral valve prolapse who had an ischemic stroke. A second CBS mutation was not identified. (less)
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Pathogenic
(Jan 28, 2003)
N
Not contributing to aggregate classification
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no assertion criteria provided
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HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED |
OMIM
Accession: SCV000020281.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
Homocystinuria In 2 unrelated patients with homocystinuria (236200), Gu et al. (1991) found a G-to-A transition in the CBS gene, resulting in a gly307-to-ser (G307S) … (more)
Homocystinuria In 2 unrelated patients with homocystinuria (236200), Gu et al. (1991) found a G-to-A transition in the CBS gene, resulting in a gly307-to-ser (G307S) substitution. Functional expression studies in E. coli showed a peptide of normal mobility that lacked CBS activity. Hu et al. (1993) found the G307S mutation in one allele of a patient of French/Scottish ancestry and in both alleles of a patient of Irish ancestry. Both parents of the second patient were heterozygotes for G307S. The mutant protein was apparently stable in expression studies in E. coli but lacked catalytic activity. Sequencing of exon 8 revealed the G307S mutation in 5 additional families. All had pyridoxine-nonresponsive homocystinuria. Hu et al. (1993) observed this mutation in 9 of 52 apparently unrelated alleles of varied ethnic backgrounds. All 9 were from patients with Celtic (Irish/English/Scottish/French) ancestry in either one or both parents. Indeed, the G307S mutation was detected in 9 of 18 Celtic alleles in their series. A second mutation found in exon 8 (I278T; 613381.0004) was associated with pyridoxine responsiveness. Gallagher et al. (1995) analyzed 17 Irish unrelated persons with homocystinuria for the G307S mutation. Homozygosity for the mutation was found in 8 of the 17. A further 8 patients were compound heterozygotes, with the G307S mutation present on 1 allele. Of the 34 alleles, 24 (71%) were G307S. Screening of newborns for homocystinuria has been routine in Ireland since 1971. Newly diagnosed infants are also assessed for responsiveness to pyridoxine; all patients analyzed by Gallagher et al. (1995) were nonresponsive. Kim et al. (1997) found a different distribution of CBS alleles in Norwegian cystinurics. The G307S mutation, which was found in 71% of mutant alleles in Ireland, accounted for only 20% in the Norwegian group and in Italian patients was not observed at all (Sperandeo et al., 1995). Hyperhomocysteinemia, Thrombotic, CBS-related In a patient with early-onset stroke and hyperhomocysteinemia without other manifestations of classic homocystinuria (see 236200), Kelly et al. (2003) identified a heterozygous G307S mutation. The patient was an 18-year-old Irish man with mitral valve prolapse who had an ischemic stroke. A second CBS mutation was not identified. (less)
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Classic homocystinuria
(Autosomal recessive inheritance)
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Child Health and Human Development Program, Research Institute of the McGill University Health Center
Accession: SCV001424905.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
show
The c.919G>A (G307S) was identified in a patient of African & French Canadian origin in compound heterozygote with c.941G>C (V314A). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had a mild intellectual impairment and does not respond to treatment with vitamin B6. (less)
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Zygosity: 1 Compound Heterozygote
Ethnicity/Population group: African and French Canadian
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not provided
(-)
N
Not contributing to aggregate classification
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no classification provided
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Classic homocystinuria |
GeneReviews
Accession: SCV002104265.2
First in ClinVar: Mar 19, 2022 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
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Citation text
Gu, Z., Ramesh, V., Kozich, V., Korson, M. S., Kraus, J. P., Shih, V. E. Identification of a molecular genetic defect in homocystinuria due to cystathionine beta-synthase deficiency. (Abstract) Am. J. Hum. Genet. 49: 406-only, 1991.
Citation text
Gu, Z., Ramesh, V., Kozich, V., Korson, M. S., Kraus, J. P., Shih, V. E. Identification of a molecular genetic defect in homocystinuria due to cystathionine beta-synthase deficiency. (Abstract) Am. J. Hum. Genet. 49: 406-only, 1991.
Comment:
The CBS c.919G>A (p.Gly307Ser) variant is well described as a common pathogenic allele in individuals with homocystinuria of Celtic origin, accounting for 71% of disease associated alleles in Ireland, 21% in the UK and 8% in the US (Moat et al. 2004). The presence of a single allele almost always predicts non-responsiveness to pyroxidine therapy. The p.Gly307Ser variant has been reported in at least six studies in which it is found in a total of 44 individuals including 14 in a homozygous state (including two pairs of siblings), ten in a compound heterozygous state (four of whom were related), and 20 heterozygotes in whom a second allele has not yet been identified (Hu et al. 1993; Gallagher et al. 1995; Kim et al. 1997; Kelly et al. 2003; Moat et al. 2004; Stabler et al. 2013). The variant was also found in at least three unaffected heterozygous relatives. The variant was absent from 82 control chromosomes but is reported at a frequency of 0.00026 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies have demonstrated that the Gly307 residue is located in the catalytic site of the protein and results in the production of correctly assembled tetramers that are slightly unfolded with a shift towards unfolded intermediates. The catalytic activity of the p.Gly307Ser variant protein is completely abolished (Hu et al. 1993; Hnizda et al. 2012). Based on the collective evidence, the p.Gly307Ser variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The p.Gly307Ser variant in CBS has been reported in at least 11 homozygous, 4 compound heterozygous and 15 heterozygous (where the second variant has not been reported) probands with homocystinuria and segregated with disease in 5 affected family members (Hu 1993, Dawson 1996, Stabler 2013, Gallagher 1995, Moat 2004). It was also reported in 1 heterozygous individual with homocystinuria and reversible cerebral white matter abnormalities who was also heterozygous for the MTHFR c.677C>T variant (Ismayilova 2019). This variant has been reported in ClinVar (ClinVar ID 117). In addition, in vitro functional studies provide evidence that the variant leads to impaired protein function (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012). This variant has also been identified in 41/129158 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_very_strong, PP1_strong, PS3_supporting.
Comment:
The p.G307S pathogenic mutation (also known as c.919G>A), located in coding exon 8 of the CBS gene, results from a G to A substitution at nucleotide position 919. The glycine at codon 307 is replaced by serine, an amino acid with similar properties. This alteration was described to account for about 70% of disease alleles in Ireland (Gallagher PM et al. Hum. Mutat., 1995;6:177-80), 21% in UK and 8% in US (Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). This alteration has been reported in the homozygous state in multiple individuals with homocysteinuria, as well as in the heterozygous state in patients with an (un)identified second allele (Dawson PA et al. Aust N Z J Med, 1996 Apr;26:180-5; Gallagher PM et al. Hum. Mutat., 1995;6:177-80; Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). In addition, this alteration was reported to occur in the enzyme active site (Meier M et al. Biochim. Biophys. Acta, 2003 Apr;1647:206-13), and in vitro studies have consistently suggested that this change would abolish enzyme activity, probably by interfering with protein folding (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hnízda A et al. J. Inherit. Metab. Dis., 2012 May;35:469-77). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CBS protein (p.Gly307Ser). This variant is present in population databases (rs121964962, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 117). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic.
Comment:
CBS: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting
Comment:
Variant summary: The CBS c.919G>A (p.Gly307Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/121292 control chromosomes at a frequency of 0.0001566, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in many affected individuals and functional study showed variant with <1% activity in comparison with WT (Kozich_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The CBS c.919G>A; p.Gly307Ser variant (rs121964962, ClinVar Variation ID: 117) is reported in the literature in numerous individuals affected with homocystinuria often found homozygous or compound heterozygous (Dawson 1996, Hu 1993, Kelly 2003, Moat 2004, Stabler 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (41/129158 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show absent or near absent enzyme activity when compared to the wildtype (Hnizda 2012, Hu 1993, Mayfield 2012). Computational analyses predict that this variant is deleterious (REVEL: 0.946). Based on available information, this variant is considered to be pathogenic. References: Dawson PA et al. Variable hyperhomocysteinaemia phenotype in heterozygotes for the Gly307Ser mutation in cystathionine beta-synthase. Aust N Z J Med. 1996 Apr;26(2):180-5. PMID: 8744616. Hnizda A et al. Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Inherit Metab Dis. 2012 May;35(3):469-77. PMID: 22069143. Hu FL et al. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet. 1993 Nov;2(11):1857-60. PMID: 7506602. Kelly PJ et al. Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology. 2003 Jan 28;60(2):275-9. PMID: 12552044. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23Epub 2012 Jan 20. Erratum in: Genetics. 2012 Oct;192(2):759-60. PMID: 22267502. Moat SJ et al. The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat. 2004 Feb;23(2):206. PMID: 14722927. Stabler SP et al. Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 2013; 11:149-63. PMID: 23733603.
Comment:
The c.919G>A variant in CBS is a missense variant predicted to cause substitution of glycine to serine at amino acid 307. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 12124992). Additionally, this variant has been observed to segregate in affected family members (PMID: 12124992). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.
Comment:
NM_000071.2(CBS):c.919G>A(G307S) is classified as pathogenic in the context of CBS-related homocystinuria, and is associated with the B6-non-responsive form of this disease. Sources cited for classification include the following: PMID 9889017, 20506325, 7506602 and 22267502. Classification of NM_000071.2(CBS):c.919G>A(G307S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Common pathogenic variant found on approximately 70% of alleles in patients of Celtic origin with homocystinuria due to cystathionine beta-synthase (CBS) deficiency and is usually associated with a more severe non-B6 responsive phenotype (Urreizti et al., 2006); Functional studies found that G307S is associated with significantly decreased CBS enzyme activity compared to wild-type (Hu et al. 1993; Kozich et al. 2010; Hnizda et al. 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 7581402, 14722927, 7564249, 17319270, 12552044, 8744616, 22267502, 23733603, 22069143, 7506602, 16479318, 30609409, 30187370, 12686134, 18280597, 12124992, 9361025, 25636110, 20506325)
Comment:
PP1, PP3_strong, PM3, PS3, PS4
Comment:
As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition.
Comment:
The CBS c.919G>A variant is predicted to result in the amino acid substitution p.Gly307Ser. This variant is one of the most commonly reported CBS variants causative for homocystinuria due to cystathionine beta-synthase deficiency (e.g., Gallagher et al. 1995. PubMed ID: 7581402; Kraus et al. 1999. PubMed ID: 10338090). In experimental studies, the p.Gly307Ser substitution has been shown to greatly impair CBS enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
The c.919G>A (G307S) was identified in a patient of African & French Canadian origin in compound heterozygote with c.941G>C (V314A). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had a mild intellectual impairment and does not respond to treatment with vitamin B6.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homocystinuria due to Cystathionine Beta-Synthase Deficiency. | Adam MP | - | 2025 | PMID: 20301697 |
| Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
| Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. | Stabler SP | JIMD reports | 2013 | PMID: 23733603 |
| Surrogate genetics and metabolic profiling for characterization of human disease alleles. | Mayfield JA | Genetics | 2012 | PMID: 22267502 |
| Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. | Hnízda A | Journal of inherited metabolic disease | 2012 | PMID: 22069143 |
| Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. | Kozich V | Human mutation | 2010 | PMID: 20506325 |
| Vascular and connective tissue features in 5 Italian patients with homocystinuria. | Evangelisti L | International journal of cardiology | 2009 | PMID: 18280597 |
| Relationship between polymorphism of cystathionine beta synthase gene and congenital heart disease in Chinese nuclear families. | Song XM | Biomedical and environmental sciences : BES | 2006 | PMID: 17319270 |
| The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. | Moat SJ | Human mutation | 2004 | PMID: 14722927 |
| Structural insights into mutations of cystathionine beta-synthase. | Meier M | Biochimica et biophysica acta | 2003 | PMID: 12686134 |
| Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. | Kelly PJ | Neurology | 2003 | PMID: 12552044 |
| The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. | Gaustadnes M | Human mutation | 2002 | PMID: 12124992 |
| Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria. | Gallagher PM | Molecular genetics and metabolism | 1998 | PMID: 9889017 |
| 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 |
| Variable hyperhomocysteinaemia phenotype in heterozygotes for the Gly307Ser mutation in cystathionine beta-synthase. | Dawson PA | Australian and New Zealand journal of medicine | 1996 | PMID: 8744616 |
| High frequency (71%) of cystathionine beta-synthase mutation G307S in Irish homocystinuria patients. | Gallagher PM | Human mutation | 1995 | PMID: 7581402 |
| Molecular analysis of patients affected by homocystinuria due to cystathionine beta-synthase deficiency: report of a new mutation in exon 8 and a deletion in intron 11. | Sperandeo MP | Journal of inherited metabolic disease | 1995 | PMID: 7564249 |
| Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. | Hu FL | Human molecular genetics | 1993 | PMID: 7506602 |
| Gu, Z., Ramesh, V., Kozich, V., Korson, M. S., Kraus, J. P., Shih, V. E. Identification of a molecular genetic defect in homocystinuria due to cystathionine beta-synthase deficiency. (Abstract) Am. J. Hum. Genet. 49: 406-only, 1991. | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS | - | - | - | - |
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Text-mined citations for rs121964962 ...
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Record last updated Jul 06, 2026
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.