Variant summary: CBS c.374G>A (p.Arg125Gln) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926), specifically in the Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site (IPR001216) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251098 control chromosomes. c.374G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example: Marble_1994, Gaustadnes_2002, Moat_2004, Melenovska_2015, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (example: Marble_1994, Melenovska_2015, Hnizda_2012). The most pronounced variant effect results in 2% enzymatic activity from transformed E. coli sourced protein (Marble_1994). Protein derived from CHO-K1 mammalian cells showed modest improvement at ~14% enzymatic activity (Melenovska_2015), although still less than 20% of normal wild-type CBS. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000071.3(CBS):c.374G>A (p.Arg125Gln)
Germline
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.
(10)
Help
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000071.3(CBS):c.374G>A (p.Arg125Gln)
Variation ID: 197625 Accession: VCV000197625.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.3 21: 43066320 (GRCh38) [ NCBI UCSC ] 21: 44486430 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 26, 2017 Jun 17, 2024 Dec 28, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000071.3:c.374G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000062.1:p.Arg125Gln missense NM_001178008.3:c.374G>A NP_001171479.1:p.Arg125Gln missense NM_001178009.3:c.374G>A NP_001171480.1:p.Arg125Gln missense NM_001320298.2:c.374G>A NP_001307227.1:p.Arg125Gln missense NM_001321072.1:c.59G>A NP_001308001.1:p.Arg20Gln missense NC_000021.9:g.43066320C>T NC_000021.8:g.44486430C>T NG_008938.1:g.14611G>A LRG_777:g.14611G>A LRG_777t1:c.374G>A LRG_777p1:p.Arg125Gln P35520:p.Arg125Gln - Protein change
- R125Q, R20Q
- Other names
- -
- Canonical SPDI
- NC_000021.9:43066319:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| CBS | - | - |
GRCh38 GRCh37 |
1287 | 1382 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 24, 2023 | RCV000178709.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 3, 2023 | RCV000723426.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 28, 2023 | RCV002228790.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2021 | RCV001804908.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 20, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230842.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810317.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Dec 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Homocystinuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002050848.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: CBS c.374G>A (p.Arg125Gln) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926), specifically in the Cysteine synthase/cystathionine … (more)
Variant summary: CBS c.374G>A (p.Arg125Gln) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926), specifically in the Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site (IPR001216) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251098 control chromosomes. c.374G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example: Marble_1994, Gaustadnes_2002, Moat_2004, Melenovska_2015, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (example: Marble_1994, Melenovska_2015, Hnizda_2012). The most pronounced variant effect results in 2% enzymatic activity from transformed E. coli sourced protein (Marble_1994). Protein derived from CHO-K1 mammalian cells showed modest improvement at ~14% enzymatic activity (Melenovska_2015), although still less than 20% of normal wild-type CBS. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227692.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM1, PM2_supporting, PM3_strong, PS3, PS4
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016935.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000649834.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 125 of the CBS protein (p.Arg125Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 125 of the CBS protein (p.Arg125Gln). This variant is present in population databases (rs781444670, gnomAD 0.005%). This missense change has been observed in individuals with homocystinuria (PMID: 7849717, 9587029, 10338090, 12124992, 21520339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197625). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 7849717, 20308073, 20506325, 22612060). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213849.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Apr 27, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000791085.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Homocystinuria due to cystathionine beta-synthase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452098.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749535.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 12-05-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 12-05-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal lens morphology (present) , Abnormal retinal morphology (present) , Hyperpigmentation of the skin (present) , Abnormal curvature of the vertebral column (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-12-05
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
PP3, PM1, PM2_supporting, PM3_strong, PS3, PS4
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 125 of the CBS protein (p.Arg125Gln). This variant is present in population databases (rs781444670, gnomAD 0.005%). This missense change has been observed in individuals with homocystinuria (PMID: 7849717, 9587029, 10338090, 12124992, 21520339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197625). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 7849717, 20308073, 20506325, 22612060). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 12-05-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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. |
Comment:
Variant summary: CBS c.374G>A (p.Arg125Gln) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926), specifically in the Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site (IPR001216) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251098 control chromosomes. c.374G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example: Marble_1994, Gaustadnes_2002, Moat_2004, Melenovska_2015, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (example: Marble_1994, Melenovska_2015, Hnizda_2012). The most pronounced variant effect results in 2% enzymatic activity from transformed E. coli sourced protein (Marble_1994). Protein derived from CHO-K1 mammalian cells showed modest improvement at ~14% enzymatic activity (Melenovska_2015), although still less than 20% of normal wild-type CBS. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP3, PM1, PM2_supporting, PM3_strong, PS3, PS4
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 125 of the CBS protein (p.Arg125Gln). This variant is present in population databases (rs781444670, gnomAD 0.005%). This missense change has been observed in individuals with homocystinuria (PMID: 7849717, 9587029, 10338090, 12124992, 21520339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197625). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 7849717, 20308073, 20506325, 22612060). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 12-05-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria. | Li DX | World journal of pediatrics : WJP | 2018 | PMID: 29508359 |
| Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. | Melenovská P | Journal of inherited metabolic disease | 2015 | PMID: 25331909 |
| Conformational properties of nine purified cystathionine β-synthase mutants. | Hnízda A | Biochemistry | 2012 | PMID: 22612060 |
| Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. | Cozar M | Human mutation | 2011 | PMID: 21520339 |
| 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 |
| Rescue of cystathionine beta-synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. | Majtan T | The Journal of biological chemistry | 2010 | PMID: 20308073 |
| Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report. | Maillot F | Journal of medical case reports | 2008 | PMID: 18423051 |
| The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. | Moat SJ | Human mutation | 2004 | PMID: 14722927 |
| 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 |
| Cystathionine beta-synthase mutations in homocystinuria. | Kraus JP | Human mutation | 1999 | PMID: 10338090 |
| Clinical aspects of cystathionine beta-synthase deficiency: how wide is the spectrum? The Italian Collaborative Study Group on Homocystinuria. | De Franchis R | European journal of pediatrics | 1998 | PMID: 9587029 |
| The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. | Sebastio G | American journal of human genetics | 1995 | PMID: 7762555 |
| Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B6 nonresponsive homocystinuria. | Marble M | Human molecular genetics | 1994 | PMID: 7849717 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS | - | - | - | - |
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Text-mined citations for rs781444670 ...
HelpThese 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 Sep 29, 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.