ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000231839 SCV000283380 uncertain significance Classic homocystinuria 2019-12-29 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.
Ambry Genetics RCV000242755 SCV000317346 uncertain significance Cardiovascular phenotype 2019-05-02 criteria provided, single submitter clinical testing Insufficient evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000514877 SCV000337364 uncertain significance not provided 2015-11-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999748 SCV000602921 uncertain significance not specified 2019-02-15 criteria provided, single submitter clinical testing The CBS c.1105C>T; p.Arg369Cys variant (rs117687681; ClinVar Variation ID: 212860) has been reported with another CBS variant in two siblings with B6 responsive homocystinuria; one was otherwise asymptomatic, the other was reported with psychiatric illness (Kim 1997). It was also identified in another B6 responsive patient with deep vein thrombosis (Gaustadness 2002). In one patient it was identified with a homozygous compound variant (p.Arg369Cys; p.Arg491Cys) to cause severe phenotype (Kluijtmas 1999). 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 may function equivalently to wild-type. This variant is fairly common in certain ethnic groups, and is found at an allele frequency of 0.5% in Czech populations (Janosik 2009) and is also found in non-Finnish European populations at a frequency of 0.48% (838/278,330 alleles, including 4 homozygotes) as listed in the Genome Aggregation Database. Based on the available information, the clinical significance of the p.Arg369Cys variant is uncertain. However, if this variant is pathogenic, it is likely associated with mild and/or adult disease, and not severe CBS deficiency. Biochemical testing for levels of homocystinuria may help clarify this result. References: Hnizda, A et al.: Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Innherit Metab dis 2012; 35:469-477. Gaustadnes M et al. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26. Janosik, M et al.: Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene. J Pediatr 2009; 154(3): 431-437. Kim et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997; 6(13): 2213-2221. Kluijtmans et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet. 1999 Jul;65(1):59-67. Kozich, V et al.: Cystathionine ?-synthase mutations: effect of mutation topology on folding and activity. Hum Mutat 2010; 31(7):809-819. Mayfield, JA et al.: Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics 2012; 190:1309-1323.
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
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.
Mendelics RCV000231839 SCV001141298 uncertain significance Classic homocystinuria 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000514877 SCV001153559 uncertain significance not provided 2020-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000231839 SCV001300403 uncertain significance Classic homocystinuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
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.

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