Submissions for variant NM_000071.3(CBS):c.833T>C (p.Ile278Thr) (rs5742905)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000078111	SCV000224772	pathogenic	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000173640	SCV000245588	pathogenic	Classic homocystinuria	2019-01-24	criteria provided, single submitter	clinical testing	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
GeneDx	RCV000078111	SCV000249694	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing	The pathogenic I278T variant in the CBS gene has been identified in nearly 25% of all CBS alleles from patients of varied ethnic backgrounds with homocystinuria due to cystathionine beta-synthase (CBS) deficiency, and has been associated with vitamin B6 responsiveness and a relatively mild clinical phenotype when homozygous (Urreizti et al., 2006).
Invitae	RCV000173640	SCV000283389	pathogenic	Classic homocystinuria	2019-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 278 of the CBS protein (p.Ile278Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs5742905, ExAC 0.2%). This variant has been reported in multiple individuals affected with homocystinuria as a homozygous or as a compound heterozygous with a different deleterious variant; and it represents the most common cause of pyridoxine responsive homocystinuria (PMID: 1301198, 19819175, 25516723, 2056790, 20567906, 18805305, 7635485, 15146473, 7611293, 11434706, 8803779, 17072863, 9708897, 10364517). ClinVar contains an entry for this variant (Variation ID: 120). Experimental studies have shown that this missense change causes low to null activity and abnormal protein folding (PMID: 1301198, 22069143, 20506325, 22267502, 11359213). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000249462	SCV000319225	pathogenic	Cardiovascular phenotype	2019-02-07	criteria provided, single submitter	clinical testing	Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Other strong data supporting pathogenic classification
Illumina Clinical Services Laboratory,Illumina	RCV000173640	SCV000436218	pathogenic	Classic homocystinuria	2017-04-27	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507410	SCV000602918	pathogenic	not specified	2018-07-23	criteria provided, single submitter	clinical testing	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 (SIFT, PolyPhen-2) predict that this variant is deleterious. 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.
Fulgent Genetics,Fulgent Genetics	RCV000173640	SCV000893555	pathogenic	Classic homocystinuria	2018-10-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000781197	SCV000919082	pathogenic	Homocystinuria	2018-01-22	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV000078111	SCV000927527	pathogenic	not provided	2018-02-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000173640	SCV001163820	pathogenic	Classic homocystinuria		criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000173640	SCV001194139	pathogenic	Classic homocystinuria	2019-12-20	criteria provided, single submitter	clinical testing	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.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000078111	SCV001246793	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001197041	SCV001367676	pathogenic	Depressivity; Impaired convergence; Gait ataxia; Intention tremor; Postural tremor; Neurodegeneration; Abnormality of the cerebral white matter; Cerebral dysmyelination; Paroxysmal vertigo; Occipital neuralgia	2018-11-06	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PM2. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001197186	SCV001367822	pathogenic	Autistic disorder of childhood onset; Cerebellar ataxia; Hallux valgus; Constipation; Bipolar affective disorder; Intellectual disability; Tremor; Intention tremor; Abnormality of brain morphology	2019-05-24	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.
OMIM	RCV000000141	SCV000020284	pathogenic	Homocystinuria, pyridoxine-responsive	2010-01-01	no assertion criteria provided	literature only
OMIM	RCV000000142	SCV000020285	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2010-01-01	no assertion criteria provided	literature only