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rs5742905

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000071.3(CBS):c.833T>C(p.Ile278Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I278S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

7
7
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:31U:1O:2

Conservation

PhyloP100: 8.10
Variant links:
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1
In a strand (size 6) in uniprot entity CBS_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000071.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868
PP5
Variant 21-43063074-A-G is Pathogenic according to our data. Variant chr21-43063074-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43063074-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBSNM_000071.3 linkuse as main transcriptc.833T>C p.Ile278Thr missense_variant 10/17 ENST00000398165.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBSENST00000398165.8 linkuse as main transcriptc.833T>C p.Ile278Thr missense_variant 10/171 NM_000071.3 P1P35520-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
0
Hom.:
0
Cov.:
0
FAILED QC
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
8
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
4
Gnomad4 NFE exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
0
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
0
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00570
Hom.:
0
ESP6500AA
AF:
0.00363
AC:
16
ESP6500EA
AF:
0.00279
AC:
24
ExAC
AF:
0.00108
AC:
131

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:31Uncertain:1Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Classic homocystinuria Pathogenic:11Other:2
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The 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. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, no assertion criteria providedclinical testingChild Health and Human Development Program, Research Institute of the McGill University Health Center-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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 12, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaMay 24, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 20, 2019NM_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. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 24, 2019The 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 -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandJun 25, 2020PS4, PM2, PM3, PM5 -
not provided, no classification providedphenotyping onlyGenomeConnect - Brain Gene Registry-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/. -
not provided Pathogenic:12
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsFeb 08, 2018- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 20, 2014- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 17, 2021Published 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) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 21, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 03, 2023- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenMar 03, 2023PS4, PP3, PS3, PM3 -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2023CBS: PM3:Very Strong, PP1:Strong, PM2, PS3:Moderate, PM5:Supporting -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2010- -
Homocystinuria Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 22, 2018Variant 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. -
Pathogenic, criteria provided, single submitterclinical testingHadassah Hebrew University Medical CenterJun 20, 2019- -
Homocystinuria, pyridoxine-responsive Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2010- -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2022The 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. -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterJan 11, 2023ACMG categories: PS3,PM1,PM2,PP3,PP5 -
Connective tissue disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 17, 2022- -
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.54
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D;D;D
Eigen
Benign
0.18
Eigen_PC
Benign
0.031
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.87
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.9
M;M;M;M
MutationTaster
Benign
0.91
A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.049
D;D;D;D
Polyphen
0.97
D;D;D;D
Vest4
0.84
MVP
0.82
MPC
1.2
ClinPred
0.99
D
GERP RS
3.5
Varity_R
0.85
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs5742905; hg19: chr21-44483184; COSMIC: COSV61442824; COSMIC: COSV61442824; API