ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1111G>A (p.Val371Met) (rs372010465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410135 SCV000486774 likely pathogenic Homocystinuria due to CBS deficiency 2016-08-05 criteria provided, single submitter clinical testing
GeneDx RCV000196393 SCV000249708 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing p.Val371Met (GTG>ATG): c.1111 G>A in exon 12 of the CBS gene (NM_000071.2). The Val371Met mutation in the CBS gene has been reported in association with homocystinuria (Kluijtmans L et al., 1995). Kluijtmans et al. reported Val371Met in one individual with homocystinuria, who also harbored another mutation in the CBS gene. Val371Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. Mutations in nearby residues (Cys370Tyr, Asp376Asn, Arg379Trp, Arg379Gln) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. In summary, Val371Met in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAAD
Invitae RCV000410135 SCV000941319 pathogenic Homocystinuria due to CBS deficiency 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 371 of the CBS protein (p.Val371Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs372010465, ExAC 0.005%). This variant has been observed in several individuals affected with homocystinuria (PMID: 10364517, 12124992, 21030686). ClinVar contains an entry for this variant (Variation ID: 212862). Experimental studies have shown that this missense change disrupts CBS protein function (PMID: 22267502). For these reasons, this variant has been classified as Pathogenic.

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