ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.700G>A (p.Asp234Asn) (rs773734233)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199941 SCV000249690 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing p.Asp234Asn (D234N) (GAC>AAC): c.700 G>A in exon 8 of the CBS gene (NM_000071.2). The pathogenic D234N variant in the CBS gene has been reported in the homozygous state and compound heterozygous state in association with homocystinuria in individuals of various ethnic backgrounds (Kraus et al., 1996; El-Said et al., 2006; De Luca et al., 2004). The D234N variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies demonstrated that D234N expression in E. coli cells reduces CBS enzyme activity and D234N expression in Hek 293 cells leads to less soluble and fewer properly assembled subunits, suggesting D234N may lead to an unstable protein that is less able to assemble into a functional enzyme (Casique et al., 2014). D234N is located in the CBS N-terminal catalytic domain at a position that is conserved across species (De Luca et al., 2004). The D234N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (A231P, H232D, E239K) have been reported in the Human Gene Mutation Database in association with homocystinuria (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret D234N as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000586183 SCV000695308 pathogenic Homocystinuria 2016-06-26 criteria provided, single submitter clinical testing Variant summary: The CBS c.700G>A (p.Asp234Asn) variant causes a missense change located in the CBS N-terminal catalytic domain at a position that is conserved across species (De Luca et al., 2004). This involves a conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "damaging" outcome, which is further supported with functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60671), which does not exceed the estimated maximal expected allele frequency for a pathogenic CBS variant of 1/328 (0.0030414). The variant of interest has been reported in multiple affected individuals via publications including 2 homozygous individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV001214144 SCV001385812 likely pathogenic Classic homocystinuria 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 234 of the CBS protein (p.Asp234Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs773734233, ExAC 0.01%). This variant has been observed in individual(s) with homocystinuria (PMID: 14972327, 16786517, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212852). This variant has been reported to affect CBS protein function (PMID: 23981774, 22267502). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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