ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1105C>T (p.Arg369Cys) (rs117687681)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000514877 SCV000602921 likely benign not provided 2018-01-05 criteria provided, single submitter clinical testing This variant (rs117687681) has been reported with another CBS variant in patients with variable mild phenotype and in one patient with homozygous compound variant [p.R369C; p.R491C] to cause severe phenotype (Janosik 2009). In addition, in vitro data indicate this variant confers impaired folding and decreased enzyme activity compared to wild-type CBS protein (Janosik 2009, Hnizda 2012, and Kozich 2010). However, the p.Arg369Cys variant has also been shown to complement CBS-negative strains of yeast (Kim 1997 and Mayfield 2012), indicating this variant likely functions equivalently to wild-type. Moreover, the p.Arg369Cys variant is fairly common in certain ethnic groups, and is found at an allele frequency of 0.5% in Czech populations (Janosik 2009). It is also listed in the in Exome Variant Server project with allele frequency in European Americans of 0.40% (identified in 34 out of 8,600 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an allele frequency in non-Finnish Europeans of 0.53% (identified in 342 out of 64,372 chromosomes, including 4 homozygotes). Lastly, the CBS gene has a high homology pseudogene (see limitations section below), and thus it is difficult to predict whether variants such as p.Arg369Cys represent mutations in the CBS gene itself, or the non-functional paralogue. We therefore suspect this variant to be benign.
Ambry Genetics RCV000242755 SCV000317346 uncertain significance Cardiovascular phenotype 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514877 SCV000610425 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000514877 SCV000337364 uncertain significance not provided 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000514877 SCV000249704 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing The R369C variant has been described in several individuals, some of whom had only mild features of CBS deficiency reported (Kim et al., 1997; Gaustadness et al., 2002). One individual harbored a second CBS variant in trans with R369C and had a relatively mild phenotype with a history of deep vein thrombosis after pregnancy but was otherwise asymptomatic (Gaustadness et al., 2002). The R369C variant has been observed in 69/10,100 (0.68%) Ashkenazi Jewish alleles, 603/125,190 (0.48%) European (non-Finnish) alleles, and has been observed as homozygous in at least 5 individuals in large population cohorts, a frequency much higher than expected for this disorder (Lek et al., 2016).The R369C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, also support a deleterious effect. Nevertheless, multiple in vitro functional analyses of this variant in various expression systems have yielded inconsistent conclusions regarding pathogenicity (Jansik et al., 2009; Kozich et al., 2010; Hnízda et al., 2012; Mayfield et al., 2012). The population data for this variant, the relatively few documented clinical cases reported considering its population frequency, and the inconsistency of functional studies make the pathogenicity of this variant uncertain.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
GenomeConnect, ClinGen RCV000514877 SCV000840352 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000514877 SCV000695300 uncertain significance not provided 2016-06-25 criteria provided, single submitter clinical testing Variant summary: The c.1105C>T (p.Arg369Cys) in CBS gene is a missense change that involves a conserved nucleotide and 5/5 in silico tools predict deleterious outcome.The variant is present in the control population dataset of ExAC at frequency of 0.0033(389/118502 chrs tested), predominantly in individuals of European origin (0.005; 342/64372 chrs tested) including 4 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.003. . This variant is reportedly very common with heterozygote frequencies in newborns of 1.6% among Norwegians , 1.0% among North Americans, and 1.0% among Czechs. The variant was identified in at-least 3 mildly affected individuals presenting with Cystathionine beta synthase deficiency (CBSD). In one patient, this variant co-occurred in cis with another potentially pathogenic misssence variant resulting in a complete loss of enzymatic activity and a severe disease phenotype. However, the sole contribution of this variant to the associated pathophysiology could not be determined. Additionally, other possible causes of homocyctinurea, such as mutations in MTHFR, MTR, MTRR and MMADHC genes have not been ruled out. Homozygotes for this R369C are B6-responsive in a corrective dose of a daily multivitamins and presented with a mild phenotype or no symptoms. This may explain the high frequency of this variant in ExAC individuals. The functional studies displayed discordant results when tested in the different expression systems. However, in all functional studies cells harboring the R369C showed moderately reduced activity and lower rate of a tetramer formation (active form). In summary, it is conceivable that in human beings the p.R369C mutation is not functionally neutral in vivo although severity and spectrum of clinical consequences is at present unknown. The variant of interest has been reported with conflicting classification in published reports: rare polymorphism (Kim, 1997) vs mild mutation (Gaustadnes, 2002) and by reputable database/clinical laboratories ranging from VUS to Pathogenic. Taking together, until more segregation data that correlate with biochemical and carrier phenotypic finding are congregated the variant was classified as VUS-possibly pathogenic.
Invitae RCV000231839 SCV000283380 uncertain significance Homocystinuria due to CBS deficiency 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 369 of the CBS protein (p.Arg369Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs117687681, ExAC 0.5%). This variant has been reported in individuals with pyridoxine-responsive homocystinuria (PMID: 9361025, 18950795, 12124992, 10364517). In one of these cases, this variant was found in trans with a pathogenic variant in CBS (PMID: 12124992). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 9361025). ClinVar contains an entry for this variant (Variation ID: 212860). Experimental studies have shown that this missense change reduces CBS activity (PMID: 18950795, 20506325, 10364517, 18708589). In summary, this variant is a missense change that has been reported in individuals affected with homocystinuria and shown to disrupt protein function in vitro. However, given its high population frequency and inconclusive segregation with disease, it has been classified as a Variant of Uncertain Significance.

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