ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1136G>A (p.Arg379Gln) (rs763036586)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169171 SCV000220402 likely pathogenic Classic homocystinuria 2014-06-11 criteria provided, single submitter literature only
GeneDx RCV000480748 SCV000566930 pathogenic not provided 2015-08-03 criteria provided, single submitter clinical testing The R379Q variant in the CBS gene was reported in one Spanish patient with severe homocystinuria, whoalso carried a second CBS variant, 1566delG (Urreizti et al., 2003). The R379Q substitution was absent form50 healthy, ethnically matched controls (Urreizti et al., 2003), and was also not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. R379Q is a semi-conservative amino acidsubstitution, which may impact secondary protein structure as these residues differ in some properties, albeitthis residue is not conserved across species. Furthermore, a missense variant in the same residue (R379W)and in nearby residues (C370Y, V371M, D376N, K384E, K384N) have been reported in the Human GeneMutation Database in association with homocystinuria (Stenson et al., 2014), supporting the functionalimportance of this residue and region of the protein. Moreover, in vitro expression in e.coli and functionalassays demonstrated that the presence of R379Q completely abolishes enzyme function, most likely due to alack of monomers to form functional tetramers (Urreizti et al., 2006). In summary, R379Q in the CBS gene is interpreted as a pathogenic variant.
Invitae RCV000169171 SCV001213253 pathogenic Classic homocystinuria 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 379 of the CBS protein (p.Arg379Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs763036586, ExAC 0.002%). This variant has been observed to be homozygous and in combination with another CBS variant in several individuals affected with homocystinuria (PMID: 16479318, 12815602, 21520339). ClinVar contains an entry for this variant (Variation ID: 188825). This variant has been reported to affect CBS protein function (PMID: 16429402). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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