Variant summary: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the protein (Hnizda_2012) and is predicted to be damaging by 5/5 in silico tools. Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012). This variant is absent in 117282 control chromosomes from ExAC. This variant is a known common pathogenic variant that causes homocystinuria. It is highly prevalent in homocystinuric patients from Spain, Portugal and South America. Genotype-phenotype correlation study show this variant leads to non-responsiveness to vitamin B6. One clinical laboratory and one reputable database (via ClinVar) have have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000071.3(CBS):c.572C>T (p.Thr191Met)
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.
(14)
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/Likely pathogenic
14
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.572C>T (p.Thr191Met)
Variation ID: 132 Accession: VCV000000132.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 21q22.3 21: 43065481 (GRCh38) [ NCBI UCSC ] 21: 44485591 (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 Apr 4, 2013 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000071.3:c.572C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000062.1:p.Thr191Met missense NM_001178008.3:c.572C>T NP_001171479.1:p.Thr191Met missense NM_001178009.3:c.572C>T NP_001171480.1:p.Thr191Met missense NM_001320298.2:c.572C>T NP_001307227.1:p.Thr191Met missense NM_001321072.1:c.257C>T NP_001308001.1:p.Thr86Met missense NC_000021.9:g.43065481G>A NC_000021.8:g.44485591G>A NG_008938.1:g.15450C>T LRG_777:g.15450C>T LRG_777t1:c.572C>T LRG_777p1:p.Thr191Met P35520:p.Thr191Met - Protein change
- T191M, T86M
- Other names
-
p.T191M:ACG>ATG
- Canonical SPDI
- NC_000021.9:43065480:G:A
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00006
- 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 (1) |
no assertion criteria provided
|
Jan 1, 2006 | RCV000000155.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000195441.8 | |
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2024 | RCV000576767.18 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2017 | RCV000589097.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2024 | RCV002227962.4 | |
|
CBS-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jan 13, 2024 | RCV003914787.3 |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 4, 2024 | RCV004018523.3 |
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
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
(Jun 05, 2017)
|
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: SCV000695307.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the … (more)
Variant summary: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the protein (Hnizda_2012) and is predicted to be damaging by 5/5 in silico tools. Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012). This variant is absent in 117282 control chromosomes from ExAC. This variant is a known common pathogenic variant that causes homocystinuria. It is highly prevalent in homocystinuric patients from Spain, Portugal and South America. Genotype-phenotype correlation study show this variant leads to non-responsiveness to vitamin B6. One clinical laboratory and one reputable database (via ClinVar) have have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790934.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841740.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000132). A different missense change at the same codon (p.Thr191Lys) has been reported to be associated with CBS related disorder (ClinVar ID: VCV000431934). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Homocystinuria (present)
|
|
|
Pathogenic
(Sep 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016940.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677987.1
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
|
|
|
Pathogenic
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512726.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting
Geographic origin: Brazil
|
|
|
Pathogenic
(Oct 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000249685.16
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., … (more)
Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., 2012; Hnzda A et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16429402, 15993874, 1281560, 29352562, 33335839, 26667307, 10338090, 20506325, 22267502, 27681349, 31589614, 16479318, 22069143, 16470595) (less)
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000769933.8
First in ClinVar: Jan 07, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 191 of the CBS protein (p.Thr191Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 191 of the CBS protein (p.Thr191Met). This variant is present in population databases (rs121964973, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 15993874, 16470595, 16479318, 25218699). ClinVar contains an entry for this variant (Variation ID: 132). 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: 10338090, 16429402, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Classic homocystinuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004213858.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003677654.3
First in ClinVar: Feb 07, 2023 Last updated: Aug 11, 2024 |
Comment:
The p.T191M pathogenic mutation (also known as c.572C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at … (more)
The p.T191M pathogenic mutation (also known as c.572C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at nucleotide position 572. The threonine at codon 191 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the homozygous state, or in conjunction with another CBS variant, in multiple individuals with CBS-related homocystinuria (Urreizti R et al. Hum Mutat, 2003 Jul;22:103; Bermúdez M et al. Hum Mutat, 2006 Mar;27:296; Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Oliveira Santos M et al. BMJ Case Rep, 2016 Sep;2016:[ePub ahead of print]; Martín-Rivada Á et al. JIMD Rep, 2022 Mar;63:146-161). Functional assays showed reduction in enzyme activity (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005331353.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Comment:
CBS: PP1:Strong, PM2, PM3, PS3:Moderate, PP3
Number of individuals with the variant: 1
|
|
|
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: SCV001452092.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jan 13, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CBS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004735389.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The CBS c.572C>T variant is predicted to result in the amino acid substitution p.Thr191Met. This variant has been reported in individuals with homocystinuria (Kraus et … (more)
The CBS c.572C>T variant is predicted to result in the amino acid substitution p.Thr191Met. This variant has been reported in individuals with homocystinuria (Kraus et al. 1999. PubMed ID: 10338090; Urreizti et al. 2003. PubMed ID: 12815602; Porto et al. 2005. PubMed ID: 15993874; Bermudez et al. 2006. PubMed ID: 16470595; Urreizti et al. 2006. PubMed ID: 16479318; Alcaide et al. 2014. PubMed ID: 25218699). Functional studies indicate that this amino acid change decreases the native folding of the encoded protein, substantially decreasing enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2011. PubMed ID: 22069143; Alcaide et al. 2014. PubMed ID: 25218699). The p.Thr191Met substitution is considered a pyridoxine non-responsive mutation (Alcaide et al. 2014. PubMed ID: 25218699). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132/). Given the evidence, we interpret CBS c.572C>T (p.Thr191Met) as pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2006)
|
no assertion criteria provided
Method: literature only
|
HOMOCYSTINURIA, PYRIDOXINE-NONRESPONSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020298.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Among 35 patients from 30 pedigrees with homocystinuria (236200) from the Iberian peninsula and several South American countries, Urreizti et al. (2006) found a high … (more)
Among 35 patients from 30 pedigrees with homocystinuria (236200) from the Iberian peninsula and several South American countries, Urreizti et al. (2006) found a high frequency of a 572C-T transition in the CBS gene, resulting in a thr191-to-met (T191M) substitution. The patients were from Spain, Portugal, Colombia, and Argentina. Combined with previously reported studies, the prevalence of T191M among mutant CBS alleles in different countries was 0.75 in Colombia, 0.52 in Spain, 0.33 in Portugal, 0.25 in Venezuela, 0.20 in Argentina, and 0.14 in Brazil. Haplotype analysis suggested a double origin for this mutation. The phenotype was B6-nonresponsive. (less)
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Comment:
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000132). A different missense change at the same codon (p.Thr191Lys) has been reported to be associated with CBS related disorder (ClinVar ID: VCV000431934). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting
Comment:
Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., 2012; Hnzda A et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16429402, 15993874, 1281560, 29352562, 33335839, 26667307, 10338090, 20506325, 22267502, 27681349, 31589614, 16479318, 22069143, 16470595)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 191 of the CBS protein (p.Thr191Met). This variant is present in population databases (rs121964973, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 15993874, 16470595, 16479318, 25218699). ClinVar contains an entry for this variant (Variation ID: 132). 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: 10338090, 16429402, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.T191M pathogenic mutation (also known as c.572C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at nucleotide position 572. The threonine at codon 191 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the homozygous state, or in conjunction with another CBS variant, in multiple individuals with CBS-related homocystinuria (Urreizti R et al. Hum Mutat, 2003 Jul;22:103; Bermúdez M et al. Hum Mutat, 2006 Mar;27:296; Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Oliveira Santos M et al. BMJ Case Rep, 2016 Sep;2016:[ePub ahead of print]; Martín-Rivada Á et al. JIMD Rep, 2022 Mar;63:146-161). Functional assays showed reduction in enzyme activity (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
CBS: PP1:Strong, PM2, PM3, PS3:Moderate, PP3
Comment:
The CBS c.572C>T variant is predicted to result in the amino acid substitution p.Thr191Met. This variant has been reported in individuals with homocystinuria (Kraus et al. 1999. PubMed ID: 10338090; Urreizti et al. 2003. PubMed ID: 12815602; Porto et al. 2005. PubMed ID: 15993874; Bermudez et al. 2006. PubMed ID: 16470595; Urreizti et al. 2006. PubMed ID: 16479318; Alcaide et al. 2014. PubMed ID: 25218699). Functional studies indicate that this amino acid change decreases the native folding of the encoded protein, substantially decreasing enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2011. PubMed ID: 22069143; Alcaide et al. 2014. PubMed ID: 25218699). The p.Thr191Met substitution is considered a pyridoxine non-responsive mutation (Alcaide et al. 2014. PubMed ID: 25218699). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132/). Given the evidence, we interpret CBS c.572C>T (p.Thr191Met) as pathogenic.
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: The CBS c.572C>T (p.Thr191Met) variant involves the alteration of a conserved nucleotide, is located in dimer interface of the active core of the protein (Hnizda_2012) and is predicted to be damaging by 5/5 in silico tools. Multiple functional studies show that this variant causes severe impairment in protein structure and/or function (Kraus_1999, Kraus_2012, Mayfield_2012). This variant is absent in 117282 control chromosomes from ExAC. This variant is a known common pathogenic variant that causes homocystinuria. It is highly prevalent in homocystinuric patients from Spain, Portugal and South America. Genotype-phenotype correlation study show this variant leads to non-responsiveness to vitamin B6. One clinical laboratory and one reputable database (via ClinVar) have have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000132). A different missense change at the same codon (p.Thr191Lys) has been reported to be associated with CBS related disorder (ClinVar ID: VCV000431934). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting
Comment:
Published functional studies demonstrate a damaging effect on protein activity and ability to form functional aggregates (Kraus JP et al., 1999; Mayfield JA et al., 2012; Hnzda A et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16429402, 15993874, 1281560, 29352562, 33335839, 26667307, 10338090, 20506325, 22267502, 27681349, 31589614, 16479318, 22069143, 16470595)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 191 of the CBS protein (p.Thr191Met). This variant is present in population databases (rs121964973, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 15993874, 16470595, 16479318, 25218699). ClinVar contains an entry for this variant (Variation ID: 132). 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: 10338090, 16429402, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.T191M pathogenic mutation (also known as c.572C>T), located in coding exon 5 of the CBS gene, results from a C to T substitution at nucleotide position 572. The threonine at codon 191 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the homozygous state, or in conjunction with another CBS variant, in multiple individuals with CBS-related homocystinuria (Urreizti R et al. Hum Mutat, 2003 Jul;22:103; Bermúdez M et al. Hum Mutat, 2006 Mar;27:296; Cozar M et al. Hum Mutat, 2011 Jul;32:835-42; Oliveira Santos M et al. BMJ Case Rep, 2016 Sep;2016:[ePub ahead of print]; Martín-Rivada Á et al. JIMD Rep, 2022 Mar;63:146-161). Functional assays showed reduction in enzyme activity (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
CBS: PP1:Strong, PM2, PM3, PS3:Moderate, PP3
Comment:
The CBS c.572C>T variant is predicted to result in the amino acid substitution p.Thr191Met. This variant has been reported in individuals with homocystinuria (Kraus et al. 1999. PubMed ID: 10338090; Urreizti et al. 2003. PubMed ID: 12815602; Porto et al. 2005. PubMed ID: 15993874; Bermudez et al. 2006. PubMed ID: 16470595; Urreizti et al. 2006. PubMed ID: 16479318; Alcaide et al. 2014. PubMed ID: 25218699). Functional studies indicate that this amino acid change decreases the native folding of the encoded protein, substantially decreasing enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2011. PubMed ID: 22069143; Alcaide et al. 2014. PubMed ID: 25218699). The p.Thr191Met substitution is considered a pyridoxine non-responsive mutation (Alcaide et al. 2014. PubMed ID: 25218699). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132/). Given the evidence, we interpret CBS c.572C>T (p.Thr191Met) as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region. | Martín-Rivada Á | JIMD reports | 2022 | PMID: 35281663 |
| Peripheral nerve involvement in classic homocystinuria: an unusual association. | Oliveira Santos M | BMJ case reports | 2016 | PMID: 27681349 |
| Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. | Alcaide P | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25218699 |
| 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 |
| Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. | Cozar M | Human mutation | 2011 | PMID: 21520339 |
| Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. | Kozich V | Human mutation | 2010 | PMID: 20506325 |
| The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America. | Urreizti R | Journal of human genetics | 2006 | PMID: 16479318 |
| High prevalence of CBS p.T191M mutation in homocystinuric patients from Colombia. | Bermúdez M | Human mutation | 2006 | PMID: 16470595 |
| Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations. | Urreizti R | Human mutation | 2006 | PMID: 16429402 |
| Molecular analysis of homocystinuria in Brazilian patients. | Porto MP | Clinica chimica acta; international journal of clinical chemistry | 2005 | PMID: 15993874 |
| Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: high prevalence of T191M and absence of I278T or G307S. | Urreizti R | Human mutation | 2003 | PMID: 12815602 |
| Cystathionine beta-synthase mutations in homocystinuria. | Kraus JP | Human mutation | 1999 | PMID: 10338090 |
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Text-mined citations for rs121964973 ...
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Record last updated Nov 25, 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.