rs5742905

chr21-43063074-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_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: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:31 U:1 O:2
• Conservation: PhyloP100: 8.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a strand (size 6) in uniprot entity CBS_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43063074-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3075863.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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
CBS	NM_000071.3	c.833T>C	p.Ile278Thr	missense_variant	10/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.833T>C	p.Ile278Thr	missense_variant	10/17	1	NM_000071.3	P1

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 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

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:31 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:11 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2019	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 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Jun 25, 2020	PS4, PM2, PM3, PM5 -
not provided, no classification provided	phenotyping only	GenomeConnect - 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/. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 24, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Child 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 Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CBS: PM3:Very Strong, PP1:Strong, PM2, PS3:Moderate, PM5:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 03, 2023	PS4, PP3, PS3, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -

Homocystinuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2018	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. -

Homocystinuria, pyridoxine-responsive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2022

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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 11, 2023

ACMG categories: PS3,PM1,PM2,PP3,PP5 -

Connective tissue disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 17, 2022

- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 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

Other links and lift over

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