ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.19dup (p.Gln7fs) (rs748695461)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409151 SCV000486905 pathogenic Classic homocystinuria 2016-09-02 criteria provided, single submitter clinical testing
GeneDx RCV000478091 SCV000567502 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The c.19dupC variant in the CBS gene has been reported previously in association with homocystinuriadue to cystathionine beta-synthase (CBS) deficiency (Kraus et al., 1999). The duplication causes aframeshift starting with codon Glutamine 7, changes this amino acid to a Proline residue and creates apremature Stop codon at position 30 of the new reading frame, denoted p.Gln7ProfsX30. This variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediatedmRNA decay. Therefore, we interpret c.19dupC as a pathogenic variant.
Invitae RCV000409151 SCV000826612 pathogenic Classic homocystinuria 2018-03-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln7Profs*30) in the CBS gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous in several individuals affected with CBS deficiency, and reported in combination with a different pathogenic CBS variant in an individual with CBS deficiency (PMID: 10338090, 12124992). ClinVar contains an entry for this variant (Variation ID: 371345). Loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000409151 SCV001163821 pathogenic Classic homocystinuria criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193390 SCV001362175 pathogenic Homocystinuria 2019-04-26 criteria provided, single submitter clinical testing Variant summary: CBS c.19dupC (p.Gln7ProfsX30) 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. The variant allele was found at a frequency of 4.1e-06 in 243178 control chromosomes (gnomAD). c.19dupC has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Homocystinuria (Alcaide_2015, Gaustadnes_2002). These data indicate that the variant is very likely to be associated with disease. A compound heterozygote affected individual was found to have <10% CBS activity (Alcaide_2015). Three ClinVar submisions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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