ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.992C>A (p.Ala331Glu) (rs777919630)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199169 SCV000249698 pathogenic not provided 2013-10-28 criteria provided, single submitter clinical testing p.Ala331Glu (GCG>GAG): c.992 C>A in exon 11 of the CBS gene (NM_000071.2). The Ala331Glu mutation in the CBS gene has been reported in association with homocystinuria (Dawson P et al., 1997). Ala331Glu results in a non-conservative amino acid substitution of a non-polar Alanine with a negatively charged Glutamic acid at a position that is conserved across species. Mutations at this residue (Ala331Val) and in nearby residues (Asp321Val, Arg336Cys, Arg336His) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Furthermore, the Ala331Glu mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Ala331Glu in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAAD
Invitae RCV000547604 SCV000649853 likely pathogenic Classic homocystinuria 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 331 of the CBS protein (p.Ala331Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with homocystinuria (PMID: 9156316, Invitae). ClinVar contains an entry for this variant (Variation ID: 212857). Experimental studies have shown that this missense change leads to a non-functional protein in vitro (PMID: 22267502, 9156316). 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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