ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1566del (p.Lys523fs) (rs786204466)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169113 SCV000220315 likely pathogenic Classic homocystinuria 2014-05-14 criteria provided, single submitter literature only
Invitae RCV000169113 SCV001230734 pathogenic Classic homocystinuria 2019-12-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CBS gene (p.Lys523Serfs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the CBS protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 12815602, 21520339). 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: 188784). This variant has been reported to affect CBS protein function (PMID: 25044645). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001175467 SCV001339042 pathogenic Homocystinuria 2020-03-19 criteria provided, single submitter clinical testing Variant summary: CBS c.1566delG (p.Lys523SerfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant was absent in 248894 control chromosomes (gnomAD). c.1566delG has been reported in the literature in individuals affected with Homocystinuria and patients who were in compound heterozygous or homozygous states displayed null CBS activity (Castro_2001, Urreizti_2003) . These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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