chr21-43063074-A-G
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
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 0Hom.: 0 Cov.: 0 FAILED QC
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 8Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 4
GnomAD4 genome 0.00 AC: 0AN: 0Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 0
ClinVar
Submissions by phenotype
Classic homocystinuria Pathogenic:13Other:2
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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/. -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
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 -
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. -
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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. -
PS4, PM2, PM3, PM5 -
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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. -
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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. -
not provided Pathogenic:13
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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) -
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. -
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PS4, PP3, PS3, PM3 -
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CBS: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:2
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
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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
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Thoracic aortic aneurysm or dissection Pathogenic:1
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
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
ACMG categories: PS3,PM1,PM2,PP3,PP5 -
Connective tissue disorder Pathogenic:1
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Intellectual disability Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at