VCV000000120.91 - ClinVar

NM_000071.3(CBS):c.833T>C (p.Ile278Thr)

Germline

Classification

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.

(37)

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

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.833T>C (p.Ile278Thr)

Variation ID: 120 Accession: VCV000000120.91

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.3 21: 43063074 (GRCh38) [ NCBI UCSC ] 21: 44483184 (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 6, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000071.3:c.833T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000062.1:p.Ile278Thr	missense
NM_001178008.3:c.833T>C	NP_001171479.1:p.Ile278Thr	missense
NM_001178009.3:c.833T>C	NP_001171480.1:p.Ile278Thr	missense
NM_001320298.2:c.833T>C	NP_001307227.1:p.Ile278Thr	missense
NM_001321072.1:c.518T>C	NP_001308001.1:p.Ile173Thr	missense
NC_000021.9:g.43063074A>G
NC_000021.8:g.44483184A>G
NG_008938.1:g.17857T>C
LRG_777:g.17857T>C
LRG_777t1:c.833T>C	LRG_777p1:p.Ile278Thr
	P35520:p.Ile278Thr

... more HGVS ... less HGVS

Protein change

I278T, I173T

Other names

p.I278T:ATT>ACT

Canonical SPDI

NC_000021.9:43063073:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00083

Links

ClinGen: CA113880 UniProtKB: P35520#VAR_002184 OMIM: 613381.0004 dbSNP: rs5742905 VarSome

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
Gene	OMIM	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.
Homocystinuria, pyridoxine-responsive	Pathogenic (1)	no assertion criteria provided	Jan 1, 2010	RCV000000141.14
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	Pathogenic (2)	criteria provided, single submitter	Jan 31, 2024	RCV000000142.18
not provided	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000078111.60
Classic homocystinuria	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000173640.49
Homocystinuria	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 20, 2019	RCV000781197.10
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001252178.10
Familial thoracic aortic aneurysm and aortic dissection	Pathogenic (1)	criteria provided, single submitter	Feb 7, 2022	RCV002310621.9
Connective tissue disorder	Pathogenic (1)	criteria provided, single submitter	May 17, 2022	RCV002276525.11
See cases	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2023	RCV003128384.8
Thoracic aortic aneurysm or dissection	Pathogenic (1)	criteria provided, single submitter	Jul 1, 2024	RCV004584135.1

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893555.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jan 22, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Homocystinuria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919082.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (9) PubMed: 8940271‚ 17540596‚ 7611293‚ 11230183‚ 14722927‚ 10364517‚ 18201569‚ 9864922‚ 16375773 Comment: Variant summary: The CBS c.833T>C (p.Ile278Thr) variant involves the alteration of a conserved nucleotide that is located in the Pyridoxal-phosphate dependent enzyme domain (InterPro). 4/4 … (more) Variant summary: The CBS c.833T>C (p.Ile278Thr) variant involves the alteration of a conserved nucleotide that is located in the Pyridoxal-phosphate dependent enzyme domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 24/30798 control chromosomes at a frequency of 0.0007793, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been found as a compound heterozygous and homozygous allele in numerous CBSD patients. It is a known common pathogenic variant when NOT found in cis with c.844_845ins68. The complex c.[833T>C;844_845ins68] is a common polymorphism found in the general population (Franco 1998, Dutta 2005, Romano 2008). The insertion variant in the complex activates an alternate splicing site, which eliminates not only the inserted intronic sequences but also the c.833T>C mutation associated with this insertion (Tsai 1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Feb 08, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Blueprint Genetics Accession: SCV000927527.1 First in ClinVar: Jul 30, 2019 Last updated: Jul 30, 2019 Comment: Patient analyzed with Aorta Panel
Pathogenic (Nov 20, 2014)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000224772.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS Number of individuals with the variant: 15 Sex: mixed
Pathogenic (Jan 24, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Classic homocystinuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000245588.3 First in ClinVar: Sep 14, 2015 Last updated: Jul 06, 2020	Publications: PubMed (4) PubMed: 23592311‚ 19819175‚ 14722927‚ 10364517 Comment: The p.Ile278Thr variant in CBS is one of the most commonly observed pathogenic variants in patients with homocystinuria (Moat 2004, Skovby 2010), has been identified … (more) The p.Ile278Thr variant in CBS is one of the most commonly observed pathogenic variants in patients with homocystinuria (Moat 2004, Skovby 2010), has been identified in more than 150 patients as both homozygotes and in trans with several additional pathogenic alleles, and segregated multiple affected relatives (Kluijtmans 1999, CBS Mutation Database: http://cbs.lf1.cuni.cz/mutations.php). It has been reported in ClinVar (Variation ID: 120). This has been identified in 0.14% (22/15362) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5742905); however there is a common insertion for which sequencing data mimics this variant, so this frequency may be inaccurate. This variant was also demonstrated to lead to reduced enzymatic activity in vitro and animal studies (Gupta 2013). In summary, this variant meets criteria to be classified as pathogenic for homocystinuria acting in a recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP1_Moderate (less) Number of individuals with the variant: 2
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Classic homocystinuria Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194139.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (8) PubMed: 11359213‚ 20506325‚ 22267502‚ 22069143‚ 1301198‚ 6711564‚ 10364517‚ 8940271 Comment: NM_000071.2(CBS):c.833T>C(I278T) is classified as pathogenic in the context of homocystinuria, CBS-related and is associated with the B6-responsive form of this disease. Sources cited for classification … (more) NM_000071.2(CBS):c.833T>C(I278T) is classified as pathogenic in the context of homocystinuria, CBS-related and is associated with the B6-responsive form of this disease. Sources cited for classification include the following: PMID 11359213, 20506325, 22267502, 22069143, 1301198, 6711564, 10364517 and 8940271. Classification of NM_000071.2(CBS):c.833T>C(I278T) 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)
Pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Homocystinuria Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001437665.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Publications: PubMed (1) PubMed: 33223529
Pathogenic (May 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367822.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3.
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: yes Allele origin: germline	3billion Accession: SCV002573187.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (3) PubMed: 20506325‚ 21520339‚ 22069143 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.083%). Functional studies provide moderate evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.083%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20506325 , 22069143). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000120). A different missense change at the same codon (p.Ile278Ser) has been reported to be associated with CBS-related disorder (PMID: 21520339). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Ectopia lentis (present) , Iridodonesis (present) , High myopia (present) , Shortened PR interval (present) , Delayed speech and language development (present) , Chronic bronchitis … (more) Ectopia lentis (present) , Iridodonesis (present) , High myopia (present) , Shortened PR interval (present) , Delayed speech and language development (present) , Chronic bronchitis (present) (less)
Pathogenic (Jan 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV003804940.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Publications: PubMed (1) PubMed: 1301198 Comment: ACMG categories: PS3,PM1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Homocystinuria (present) Age: 50-59 years Sex: female Tissue: blood
Pathogenic (Mar 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026267.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS4, PP3, PS3, PM3
Pathogenic (Apr 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016938.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thoracic aortic aneurysm or dissection Affected status: yes Allele origin: germline	NHS Central & South Genomic Laboratory Hub Accession: SCV005068242.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024
Pathogenic (Feb 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197393.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Classic homocystinuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000436218.3 First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019	Publications: PubMed (8) PubMed: 8940271‚ 19819175‚ 10338090‚ 10807759‚ 7611293‚ 10328723‚ 14722927‚ 10364517 Comment: The CBS c.833T>C (p.Ile278Thr) variant is the most common variant associated with homocystinuria, overall accounting for 25% of all pathogenic variants, including 29% of the … (more) The CBS c.833T>C (p.Ile278Thr) variant is the most common variant associated with homocystinuria, overall accounting for 25% of all pathogenic variants, including 29% of the variant alleles in the UK and 18% in the US. In the Netherlands it was shown to account for the majority of pathogenic variants for homocystinuria (Gaustadnes et al. 1999; Kluijtmans et al. 1999; Moat et al. 2004; Skovby et al. 2010). The p.Ile278Thr variant is associated with reduced CBS activity and responsiveness to vitamin B6 (Shih et al. 1995; Gaustadnes et al. 1999; Kluijtmans et al. 1999). Individuals who are homozygous for the p.Ile278Thr variant are generally mildly affected and tend to be diagnosed as adults (Gaustadnes et al. 2000; Skovby et al. 2010). Those who are compound heterozygous for the p.Ile278Thr variant have variable phenotypes, ranging from mild to severe disease (Kraus et al. 1999). The p.Ile278Thr variant is most commonly found in cis with an intronic insertion variant in the CBS gene, c.844ins68, which introduces a novel splice site, causing excision of the p.Ile278Thr variant itself, resulting in a nonpathogenic allele (Tsai et al. 1996). Thus, the frequency of the p.Ile278Thr allele in the general population is likely to be higher than the incidence of homocystinuria would indicate. The variant is reported at a frequency of 0.00353 in the African American population of the Exome Sequencing Project. Based on the collective evidence, the p.Ile278Thr 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)
Pathogenic (Jun 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: no Allele origin: germline	Clinical Genetics Laboratory, Region Ostergotland Accession: SCV001977085.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 Comment: Heterozygous	Comment: PS4, PM2, PM3, PM5
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000249694.16 First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect (Hnizda et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein … (more) Published functional studies demonstrate a damaging effect (Hnizda 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: 20567906, 21917271, 19819175, 20981092, 18805305, 11434706, 8803779, 14722927, 8554066, 9708897, 7635485, 15972722, 15748616, 8755636, 30609409, 7611293, 16479318, 1301198, 23592311, 25087612, 22267502, 22995991, 20506325, 26750749, 12552044, 29326875, 15146473, 17072863, 10364517, 25516723, 28152038, 29044829, 7506602, 7762555, 10328723, 11359213, 20301697, 11748855, 10807759, 10338090, 8940271, 6711564, 30021915, 30487145, 23430030, 25636110, 32820583, 22069143, 31589614, 34426522, 27535533) (less)
Pathogenic (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566538.2 First in ClinVar: Aug 29, 2022 Last updated: Mar 26, 2023
Pathogenic (May 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715596.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (8) PubMed: 1301198‚ 14722927‚ 19819175‚ 20567906‚ 22069143‚ 22267502‚ 7611293‚ 7635485 Number of individuals with the variant: 84
Pathogenic (Sep 21, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602918.4 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The CBS c.833T>C; p.Ile278Thr variant (rs5742905) is the most frequently reported variant associated with pyridoxine-responsive homocystinuria and has been observed in affected individuals in both … (more) The CBS c.833T>C; p.Ile278Thr variant (rs5742905) is the most frequently reported variant associated with pyridoxine-responsive homocystinuria and has been observed in affected individuals in both the homozygous and compound heterozygous states (Gaustadnes 1999, Refsum 2004, Skovby 2010, Magner, 2011, and Sorensen 2016). Functional studies demonstrate that the p.Ile278Thr variant has decreased stability and severely reduced activity relative to wildtype protein (Kozich 2010, Hnizda 2012, and Mayfield 2012). The clinical presentation of p.Ile278Thr homozygotes has been described as mild, with many patients having thrombosis as their initial symptom (Skovby 2010). This variant is classified as pathogenic in ClinVar (ID: 120) and is found in the general population with an overall allele frequency of 0.08% (24/30774 alleles) in the Genome Aggregation Database. The isoleucine at codon 278 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.74). Based on the available evidence, the p.Ile278Thr variant is considered to be pathogenic. References: Gaustadnes et al, Prevalence of congenital homocystinuria in Denmark. N Engl J Med. 1999 May 13;340(19):1513. Hnizda 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; 35(3):469-477 Kozich et al. Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. Hum Mutat. 2010; 31(7):809-819. Magner et al. Vascular presentation of cystathionine beta-synthase deficiency in adulthood. J Inherit Metab Dis. 2011; 34(1):33-37. Mayfield et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23. Refsum et al. Birth prevalence of homocystinuria. J Pediatr. 2004 Jun;144(6):830-2. Skovby et al. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010; 99(1):1-3. Sorensen et al. Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Mol Genet Metab. 2016; 117(3):344-350. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283389.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024	Publications: PubMed (19) PubMed: 28492532‚ 1301198‚ 2056790‚ 7611293‚ 7635485‚ 8803779‚ 9708897‚ 10364517‚ 11434706‚ 15146473‚ 17072863‚ 18805305‚ 19819175‚ 20567906‚ 25516723‚ 11359213‚ 20506325‚ 22069143‚ 22267502 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 278 of the CBS protein (p.Ile278Thr). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 278 of the CBS protein (p.Ile278Thr). This variant is present in population databases (rs5742905, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyridoxine responsive homocystinuria (PMID: 1301198, 2056790, 7611293, 7635485, 8803779, 9708897, 10364517, 11434706, 15146473, 17072863, 18805305, 19819175, 20567906, 25516723). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 120). 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: 1301198, 11359213, 20506325, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 07, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000319225.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26750749 Comment: The p.I278T pathogenic mutation (also known as c.833T>C), located in coding exon 8 of the CBS gene, results from a T to C substitution at … (more) The p.I278T pathogenic mutation (also known as c.833T>C), located in coding exon 8 of the CBS gene, results from a T to C substitution at nucleotide position 833. The isoleucine at codon 278 is replaced by threonine. This prevalent panethnic mutation is associated with pyridoxine responsiveness and a mild clinical phenotype in homozygotes and compound heterozygotes (Shih VE et al. Am J Hum Genet. 1995;57(1):34-9; Sørensen JT et al. Mol. Genet. Metab., 2016 Mar;117:344-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Classic homocystinuria Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052059.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001163820.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246793.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CBS: PM3:Very Strong, PM2, PM5:Supporting Number of individuals with the variant: 9
Uncertain significance (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427928.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Publications: PubMed (1) PubMed: 25741868
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Classic homocystinuria (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Child Health and Human Development Program, Research Institute of the McGill University Health Center Accession: SCV001424574.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Comment: The c.833C>T (I278T) was identified as a compound heterozygote with IVS11-2 A>C in a patient of Eastern European origin. Clinical characteristics included lens dislocation and … (more) The c.833C>T (I278T) was identified as a compound heterozygote with IVS11-2 A>C in a patient of Eastern European origin. Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had no intellectual impairment and does not respond to treatment with vitamin B6. (less) Comment on evidence: The c.833C>T (I278T) was identified as a compound heterozygote with IVS11-2 A>C in a patient of Eastern European origin.
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: SCV001462118.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001808111.2 First in ClinVar: Aug 27, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980521.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Jan 01, 2010)	no assertion criteria provided Method: literature only	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020285.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (10) PubMed: 7506602‚ 1301198‚ 7611293‚ 8554066‚ 10364517‚ 7762555‚ 10328723‚ 28583326‚ 19819175‚ 12552044 Comment on evidence: Homocystinuria On both alleles of a pyridoxine-responsive Polish patient with homocystinuria, Hu et al. (1993) identified an 833T-C transition in exon 8 of the CBS … (more) Homocystinuria On both alleles of a pyridoxine-responsive Polish patient with homocystinuria, Hu et al. (1993) identified an 833T-C transition in exon 8 of the CBS gene, resulting in an ile278-to-thr (I278T) substitution. They also identified this mutation on 1 allele of a pyridoxine-nonresponsive Polish patient. In a mildly affected pyridoxine-responsive patient of Ashkenazi Jewish origin, Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation and a paternal IVS11-2A-C mutation (613381.0012). By PCR amplification and sequencing of exon 8 from genomic DNA, Shih et al. (1995) detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine-responsiveness and in none of 27 pyridoxine-nonresponsive patients; 2 pyridoxine-responsive patients were homozygous and 5 were heterozygous for I278T. They further observed the I278T mutation in 9 (41%) of 22 independent alleles in pyridoxine-responsive patients of various ethnic backgrounds. In 2 of the compound heterozygotes, they identified novel mutations (G139R, 613381.0005 and E144K, 613381.0006) on the other allele. The 2 patients who were homozygous for I278T had only ectopia lentis and mild bone demineralization. Shih et al. (1995) concluded that compound heterozygous patients who have one copy of the I278T mutation are likely to retain some degree of pyridoxine responsiveness. Although the 833T-C mutation is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, Kluijtmans et al. (1996) found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. In a study of 21 unrelated Dutch pedigrees, Kluijtmans et al. (1999) found that of 10 different mutations detected in the CBS gene, I278T was predominant, being present in 23 (55%) of 42 independent alleles. Homozygotes for this mutation tended to have higher homocysteine levels than those in patients with other genotypes, but similar clinical manifestations. I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment at least 30 would have been expected. The I278T mutation is the most frequent mutation in homocystinuria in Italy, where most cases are B6-responsive and the disorder has a total frequency of approximately 1 in 55,000 as compared with a frequency of 1 in 58,000 in the United States and 1 in 889,000 in Japan (Sebastio, 1997). Gaustadnes et al. (1999) stated that the I278T mutation is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). A surprisingly high prevalence of the 833T-C mutation was detected among newborns, suggesting that the incidence of homocystinuria due to homozygosity for this mutation may be at least 1 per 20,500 live births in Denmark. In a study of 11 families in the state of Georgia (USA), Kruger et al. (2003) found that the I278T and T353M (613381.0015) mutations accounted for 45% of the mutant alleles. The T353M mutation, found exclusively in 4 African American patients, was associated with a B6-nonresponsive phenotype and detection by neonatal screening for hypermethioninemia. The I278T mutation was found exclusively in Caucasian patients and was associated with a B6-responsive phenotype. In a population-based study in Denmark, Skovby et al. (2010) concluded that the predominant portion of individuals who are homozygous for the I278T mutation may be clinically unaffected or may only be ascertained after the third decade due to a thromboembolic event. These individuals do not have most of the clinical features of complete CBS deficiency. Hyperhomocysteinemia, Thrombotic, CBS-related In a patient with early-onset stroke and hyperhomocysteinemia without other classic features of homocystinuria (see 236200), Kelly et al. (2003) identified a heterozygous I278T mutation. The patient was a 47-year-old white woman of northern European descent with a thrombus in the right internal carotid artery. Kelly et al. (2003) postulated that she might have another, unidentified CBS mutation. (less)
Pathogenic (Jan 01, 2010)	no assertion criteria provided Method: literature only	HOMOCYSTINURIA, PYRIDOXINE-RESPONSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020284.5 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (10) PubMed: 7506602‚ 1301198‚ 7611293‚ 8554066‚ 10364517‚ 7762555‚ 10328723‚ 28583326‚ 19819175‚ 12552044 Comment on evidence: Homocystinuria On both alleles of a pyridoxine-responsive Polish patient with homocystinuria, Hu et al. (1993) identified an 833T-C transition in exon 8 of the CBS … (more) Homocystinuria On both alleles of a pyridoxine-responsive Polish patient with homocystinuria, Hu et al. (1993) identified an 833T-C transition in exon 8 of the CBS gene, resulting in an ile278-to-thr (I278T) substitution. They also identified this mutation on 1 allele of a pyridoxine-nonresponsive Polish patient. In a mildly affected pyridoxine-responsive patient of Ashkenazi Jewish origin, Kozich and Kraus (1992) identified compound heterozygosity for a maternal I278T mutation and a paternal IVS11-2A-C mutation (613381.0012). By PCR amplification and sequencing of exon 8 from genomic DNA, Shih et al. (1995) detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine-responsiveness and in none of 27 pyridoxine-nonresponsive patients; 2 pyridoxine-responsive patients were homozygous and 5 were heterozygous for I278T. They further observed the I278T mutation in 9 (41%) of 22 independent alleles in pyridoxine-responsive patients of various ethnic backgrounds. In 2 of the compound heterozygotes, they identified novel mutations (G139R, 613381.0005 and E144K, 613381.0006) on the other allele. The 2 patients who were homozygous for I278T had only ectopia lentis and mild bone demineralization. Shih et al. (1995) concluded that compound heterozygous patients who have one copy of the I278T mutation are likely to retain some degree of pyridoxine responsiveness. Although the 833T-C mutation is found in 50% of the CBS alleles in Dutch homozygous CBS-deficient patients, Kluijtmans et al. (1996) found it in none of 60 patients with premature cardiovascular disease. This led them to conclude that heterozygosity for CBS deficiency is not involved in premature cardiovascular disease. In a study of 21 unrelated Dutch pedigrees, Kluijtmans et al. (1999) found that of 10 different mutations detected in the CBS gene, I278T was predominant, being present in 23 (55%) of 42 independent alleles. Homozygotes for this mutation tended to have higher homocysteine levels than those in patients with other genotypes, but similar clinical manifestations. I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment at least 30 would have been expected. The I278T mutation is the most frequent mutation in homocystinuria in Italy, where most cases are B6-responsive and the disorder has a total frequency of approximately 1 in 55,000 as compared with a frequency of 1 in 58,000 in the United States and 1 in 889,000 in Japan (Sebastio, 1997). Gaustadnes et al. (1999) stated that the I278T mutation is geographically widespread. They determined the frequency of this mutation among Danish newborns by screening 500 consecutive Guthrie cards (specimens of infants' blood collected on filter paper). A surprisingly high prevalence of the 833T-C mutation was detected among newborns, suggesting that the incidence of homocystinuria due to homozygosity for this mutation may be at least 1 per 20,500 live births in Denmark. In a study of 11 families in the state of Georgia (USA), Kruger et al. (2003) found that the I278T and T353M (613381.0015) mutations accounted for 45% of the mutant alleles. The T353M mutation, found exclusively in 4 African American patients, was associated with a B6-nonresponsive phenotype and detection by neonatal screening for hypermethioninemia. The I278T mutation was found exclusively in Caucasian patients and was associated with a B6-responsive phenotype. In a population-based study in Denmark, Skovby et al. (2010) concluded that the predominant portion of individuals who are homozygous for the I278T mutation may be clinically unaffected or may only be ascertained after the third decade due to a thromboembolic event. These individuals do not have most of the clinical features of complete CBS deficiency. Hyperhomocysteinemia, Thrombotic, CBS-related In a patient with early-onset stroke and hyperhomocysteinemia without other classic features of homocystinuria (see 236200), Kelly et al. (2003) identified a heterozygous I278T mutation. The patient was a 47-year-old white woman of northern European descent with a thrombus in the right internal carotid artery. Kelly et al. (2003) postulated that she might have another, unidentified CBS mutation. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742388.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923876.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001951383.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Classic homocystinuria Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV002104264.2 First in ClinVar: Mar 19, 2022 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1524 BookShelf: NBK1524
not provided (-)	no classification provided Method: phenotyping only	Classic homocystinuria Affected status: unknown Allele origin: paternal	GenomeConnect - Brain Gene Registry Accession: SCV004176870.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: Variant classified as Pathogenic and reported on 04-10-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does … (more) Variant classified as Pathogenic and reported on 04-10-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Orthostatic tachycardia (present) , Compulsive behaviors (present) , Anxiety (present) , Feeding difficulties (present) , Encephalopathy (present) , Specific learning disability (present) , High palate … (more) Orthostatic tachycardia (present) , Compulsive behaviors (present) , Anxiety (present) , Feeding difficulties (present) , Encephalopathy (present) , Specific learning disability (present) , High palate (present) , Abnormality of the temporomandibular joint (present) , Scoliosis (present) , Slender build (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2020-04-10 Testing laboratory interpretation: Pathogenic
click to load more click to collapse

Comment:

Variant summary: The CBS c.833T>C (p.Ile278Thr) variant involves the alteration of a conserved nucleotide that is located in the Pyridoxal-phosphate dependent enzyme domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 24/30798 control chromosomes at a frequency of 0.0007793, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been found as a compound heterozygous and homozygous allele in numerous CBSD patients. It is a known common pathogenic variant when NOT found in cis with c.844_845ins68. The complex c.[833T>C;844_845ins68] is a common polymorphism found in the general population (Franco 1998, Dutta 2005, Romano 2008). The insertion variant in the complex activates an alternate splicing site, which eliminates not only the inserted intronic sequences but also the c.833T>C mutation associated with this insertion (Tsai 1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The p.Ile278Thr variant in CBS is one of the most commonly observed pathogenic variants in patients with homocystinuria (Moat 2004, Skovby 2010), has been identified in more than 150 patients as both homozygotes and in trans with several additional pathogenic alleles, and segregated multiple affected relatives (Kluijtmans 1999, CBS Mutation Database: http://cbs.lf1.cuni.cz/mutations.php). It has been reported in ClinVar (Variation ID: 120). This has been identified in 0.14% (22/15362) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5742905); however there is a common insertion for which sequencing data mimics this variant, so this frequency may be inaccurate. This variant was also demonstrated to lead to reduced enzymatic activity in vitro and animal studies (Gupta 2013). In summary, this variant meets criteria to be classified as pathogenic for homocystinuria acting in a recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP1_Moderate

Comment:

NM_000071.2(CBS):c.833T>C(I278T) is classified as pathogenic in the context of homocystinuria, CBS-related and is associated with the B6-responsive form of this disease. Sources cited for classification include the following: PMID 11359213, 20506325, 22267502, 22069143, 1301198, 6711564, 10364517 and 8940271. Classification of NM_000071.2(CBS):c.833T>C(I278T) 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:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.083%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20506325 , 22069143). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000120). A different missense change at the same codon (p.Ile278Ser) has been reported to be associated with CBS-related disorder (PMID: 21520339). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The CBS c.833T>C (p.Ile278Thr) variant is the most common variant associated with homocystinuria, overall accounting for 25% of all pathogenic variants, including 29% of the variant alleles in the UK and 18% in the US. In the Netherlands it was shown to account for the majority of pathogenic variants for homocystinuria (Gaustadnes et al. 1999; Kluijtmans et al. 1999; Moat et al. 2004; Skovby et al. 2010). The p.Ile278Thr variant is associated with reduced CBS activity and responsiveness to vitamin B6 (Shih et al. 1995; Gaustadnes et al. 1999; Kluijtmans et al. 1999). Individuals who are homozygous for the p.Ile278Thr variant are generally mildly affected and tend to be diagnosed as adults (Gaustadnes et al. 2000; Skovby et al. 2010). Those who are compound heterozygous for the p.Ile278Thr variant have variable phenotypes, ranging from mild to severe disease (Kraus et al. 1999). The p.Ile278Thr variant is most commonly found in cis with an intronic insertion variant in the CBS gene, c.844ins68, which introduces a novel splice site, causing excision of the p.Ile278Thr variant itself, resulting in a nonpathogenic allele (Tsai et al. 1996). Thus, the frequency of the p.Ile278Thr allele in the general population is likely to be higher than the incidence of homocystinuria would indicate. The variant is reported at a frequency of 0.00353 in the African American population of the Exome Sequencing Project. Based on the collective evidence, the p.Ile278Thr 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:

Published functional studies demonstrate a damaging effect (Hnizda 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: 20567906, 21917271, 19819175, 20981092, 18805305, 11434706, 8803779, 14722927, 8554066, 9708897, 7635485, 15972722, 15748616, 8755636, 30609409, 7611293, 16479318, 1301198, 23592311, 25087612, 22267502, 22995991, 20506325, 26750749, 12552044, 29326875, 15146473, 17072863, 10364517, 25516723, 28152038, 29044829, 7506602, 7762555, 10328723, 11359213, 20301697, 11748855, 10807759, 10338090, 8940271, 6711564, 30021915, 30487145, 23430030, 25636110, 32820583, 22069143, 31589614, 34426522, 27535533)

Comment:

The CBS c.833T>C; p.Ile278Thr variant (rs5742905) is the most frequently reported variant associated with pyridoxine-responsive homocystinuria and has been observed in affected individuals in both the homozygous and compound heterozygous states (Gaustadnes 1999, Refsum 2004, Skovby 2010, Magner, 2011, and Sorensen 2016). Functional studies demonstrate that the p.Ile278Thr variant has decreased stability and severely reduced activity relative to wildtype protein (Kozich 2010, Hnizda 2012, and Mayfield 2012). The clinical presentation of p.Ile278Thr homozygotes has been described as mild, with many patients having thrombosis as their initial symptom (Skovby 2010). This variant is classified as pathogenic in ClinVar (ID: 120) and is found in the general population with an overall allele frequency of 0.08% (24/30774 alleles) in the Genome Aggregation Database. The isoleucine at codon 278 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.74). Based on the available evidence, the p.Ile278Thr variant is considered to be pathogenic. References: Gaustadnes et al, Prevalence of congenital homocystinuria in Denmark. N Engl J Med. 1999 May 13;340(19):1513. Hnizda 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; 35(3):469-477 Kozich et al. Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. Hum Mutat. 2010; 31(7):809-819. Magner et al. Vascular presentation of cystathionine beta-synthase deficiency in adulthood. J Inherit Metab Dis. 2011; 34(1):33-37. Mayfield et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23. Refsum et al. Birth prevalence of homocystinuria. J Pediatr. 2004 Jun;144(6):830-2. Skovby et al. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010; 99(1):1-3. Sorensen et al. Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Mol Genet Metab. 2016; 117(3):344-350.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 278 of the CBS protein (p.Ile278Thr). This variant is present in population databases (rs5742905, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyridoxine responsive homocystinuria (PMID: 1301198, 2056790, 7611293, 7635485, 8803779, 9708897, 10364517, 11434706, 15146473, 17072863, 18805305, 19819175, 20567906, 25516723). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 120). 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: 1301198, 11359213, 20506325, 22069143, 22267502). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.I278T pathogenic mutation (also known as c.833T>C), located in coding exon 8 of the CBS gene, results from a T to C substitution at nucleotide position 833. The isoleucine at codon 278 is replaced by threonine. This prevalent panethnic mutation is associated with pyridoxine responsiveness and a mild clinical phenotype in homozygotes and compound heterozygotes (Shih VE et al. Am J Hum Genet. 1995;57(1):34-9; Sørensen JT et al. Mol. Genet. Metab., 2016 Mar;117:344-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The c.833C>T (I278T) was identified as a compound heterozygote with IVS11-2 A>C in a patient of Eastern European origin. Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had no intellectual impairment and does not respond to treatment with vitamin B6.

Comment:

Variant classified as Pathogenic and reported on 04-10-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child.	Mor-Shaked H	European journal of human genetics : EJHG	2021	PMID: 33223529
Cystathionine β-synthase deficiency: Of mice and men.	Kruger WD	Molecular genetics and metabolism	2017	PMID: 28583326
Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency.	Adam MP	-	2017	PMID: 20301697
Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia.	Sørensen JT	Molecular genetics and metabolism	2016	PMID: 26750749
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis.	Awan Z	Thrombosis journal	2014	PMID: 25516723
Correction of cystathionine β-synthase deficiency in mice by treatment with proteasome inhibitors.	Gupta S	Human mutation	2013	PMID: 23592311
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
Vascular presentation of cystathionine beta-synthase deficiency in adulthood.	Magner M	Journal of inherited metabolic disease	2011	PMID: 20567906
Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity.	Kozich V	Human mutation	2010	PMID: 20506325
A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency.	Skovby F	Molecular genetics and metabolism	2010	PMID: 19819175
[Stroke and iridodonesis revealing a homocystinuria caused by a compound heterozygous mutation of cystathionine beta-synthase].	Lefaucheur R	Revue neurologique	2008	PMID: 18805305
Origin and evolution of the c.844_845ins68/c.833T>C mutations within the cystathionine beta-synthase gene in great apes.	Romano M	FEBS letters	2008	PMID: 18201569
Chemical chaperone rescue of mutant human cystathionine beta-synthase.	Singh LR	Molecular genetics and metabolism	2007	PMID: 17540596
Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.	Vyletal P	Human mutation	2007	PMID: 17072863
Cystathionine beta-synthase T833C/844INS68 polymorphism: a family-based study on mentally retarded children.	Dutta S	Behavioral and brain functions : BBF	2005	PMID: 16375773
Identification and functional analysis of two novel mutations in the CBS gene in Polish patients with homocystinuria.	Orendáè M	Human mutation	2004	PMID: 15146473
The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria.	Moat SJ	Human mutation	2004	PMID: 14722927
Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.	Kelly PJ	Neurology	2003	PMID: 12552044
High prevalence of the I278T mutation of the human cystathionine beta-synthase detected by a novel screening application.	Linnebank M	Thrombosis and haemostasis	2001	PMID: 11434706
Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria.	Janosík M	American journal of human genetics	2001	PMID: 11359213
Mutations in the regulatory domain of cystathionine beta synthase can functionally suppress patient-derived mutations in cis.	Shan X	Human molecular genetics	2001	PMID: 11230183
Familial thrombophilia associated with homozygosity for the cystathionine beta-synthase 833T-->C mutation.	Gaustadnes M	Arteriosclerosis, thrombosis, and vascular biology	2000	PMID: 10807759
The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment.	Kluijtmans LA	American journal of human genetics	1999	PMID: 10364517
Cystathionine beta-synthase mutations in homocystinuria.	Kraus JP	Human mutation	1999	PMID: 10338090
Prevalence of congenital homocystinuria in Denmark.	Gaustadnes M	The New England journal of medicine	1999	PMID: 10328723
The frequency of 844ins68 mutation in the cystathionine beta-synthase gene is not increased in patients with venous thrombosis.	Franco R	Haematologica	1998	PMID: 9864922
Detection of a novel deletion in the cystathionine beta-synthase (CBS) gene using an improved genomic DNA based method.	Gaustadnes M	FEBS letters	1998	PMID: 9708897
High prevalence of a mutation in the cystathionine beta-synthase gene.	Tsai MY	American journal of human genetics	1996	PMID: 8940271
Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations.	Sperandeo MP	Journal of inherited metabolic disease	1996	PMID: 8803779
Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.	Kluijtmans LA	American journal of human genetics	1996	PMID: 8554066
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
Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients.	Kluijtmans LA	Human genetics	1995	PMID: 7635485
A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype.	Shih VE	American journal of human genetics	1995	PMID: 7611293
Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria.	Hu FL	Human molecular genetics	1993	PMID: 7506602
Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency.	Kozich V	Human mutation	1992	PMID: 1301198
[Hospital outbreak of salmonellosis with secondary cases].	Bellido Blasco J	Medicina clinica	1991	PMID: 2056790
Homocystinuria: biogenesis of cystathionine beta-synthase subunits in cultured fibroblasts and in an in vitro translation system programmed with fibroblast messenger RNA.	Skovby F	American journal of human genetics	1984	PMID: 6711564
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CBS	-	-	-	-
click to load more click to collapse

Text-mined citations for rs5742905 ...

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

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000071.3(CBS):c.833T>C (p.Ile278Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5742905 ...