ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.341C>T (p.Ala114Val) (rs121964964)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000490533 SCV000678069 likely pathogenic Homocystinuria due to CBS deficiency 2017-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000490533 SCV000893556 pathogenic Homocystinuria due to CBS deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000200823 SCV000249676 pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing p.Ala114Val (A114V) (GCG>GTG): c.341 C>T in exon 5 of the CBS gene (NM_000071.2). The A114V mutation in the CBS gene has been reported in at least 4 individuals in association with homocystinuria (Kozich et al.,1993; Sebastio et al., 1995). The A114V mutation is a conservative amino acid substitution, as these residues share similar properties, and are least likely to impact secondary structure. However, functional studies have shown A114V leads to protein misfolding and instability compared to wild-type alleles (Kozich et al., 2010; Hznida et al., 2012). Additionally, mutations in nearby residues (C109R, G116R) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Finally, the A114V mutation was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the 1000 Genomes Project (McVean et al., 2012). In summary, A114V in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-PANCARD,TAAD,TAADV2-1
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000490533 SCV000746328 pathogenic Homocystinuria due to CBS deficiency 2017-12-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590659 SCV000695305 pathogenic Homocystinuria 2016-01-26 criteria provided, single submitter clinical testing Variant summary: The c.341C>T in CBS gene is a missense variant that involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC ans ESP projects at an allele frequency of 0.027%. This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in CBS (0.3%).suggesting this variant is not a common polymorphism. The variant has been reported in several affected individuals presented with features suggestive of Cystathionine--synthase deficiency. Functional studies performed in bacteria-based system showed slight misfolding of the recombinant protein and low enzymatic activity. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers.Taking together, the variant was classified as Pathogenic.
Invitae RCV000490533 SCV000956328 pathogenic Homocystinuria due to CBS deficiency 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 114 of the CBS protein (p.Ala114Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121964964, ExAC 0.03%). This variant has been observed in an individual with low cystathionine- beta synthase enzyme activity, findings that are highly specific for homocystinuria due to cystathionine-beta synthase (CBS) deficiency (PMID: 8353501). It has also been reported in individuals with a clinical diagnosis of cystathionine-beta synthase deficiency (PMID: 7762555) ClinVar contains an entry for this variant (Variation ID: 119). Experimental studies have shown that this missense change disrupts CBS protein activity (PMID: 20490928, 22612060, 22267502, 22069143, 20506325). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000140 SCV000020283 pathogenic Homocystinuria, pyridoxine-responsive 1993-06-01 no assertion criteria provided literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490533 SCV000267240 likely pathogenic Homocystinuria due to CBS deficiency 2016-03-18 criteria provided, single submitter reference population

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