ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.667-14_667-7del (rs764160782)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169271 SCV000220572 likely pathogenic Classic homocystinuria 2014-08-01 criteria provided, single submitter literature only
GeneDx RCV000274429 SCV000329209 pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing The c.667-14_667-7delCTCTTTCT variant has been described in two siblings with severe homocystinuria due to cystathionine beta-synthase (CBS) deficiency who were also heterozygous for another variant in the CBS gene (Cozar et al., 2011). Functional analysis found that c.667-14_667-7delCTCTTTCT results in exon 6 skipping and produces a frameshift (Cozar et al., 2011). The c.667-14_667-7delCTCTTTCT variant was not observed in approximately 6500 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, we interpret c.667-14_667-7delCTCTTTCT to be a pathogenic variant.
Invitae RCV000169271 SCV000769931 likely pathogenic Classic homocystinuria 2019-10-01 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the CBS gene. It does not directly change the encoded amino acid sequence of the CBS protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs764160782, ExAC 0.002%). This variant has been observed in individual(s) with homocystinuria (PMID: 21520339, 28980096, Invitae). 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: 188911). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 21520339). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780083 SCV000917109 likely pathogenic Homocystinuria 2018-12-24 criteria provided, single submitter clinical testing Variant summary: CBS c.667-14_667-7delCTCTTTCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 3' acceptor site, while two predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating exon 6 skipping in a minigene assay that would produce a frameshift (Cozar 2011). This variant was named using the reference sequence NG_008938.1; cDNA, ENST00000352178 in this report. The variant allele was found at a frequency of 7.2e-06 in 277014 control chromosomes (gnomAD). c.667-14_667-7delCTCTTTCT has been reported in the literature in two compound heterozygous siblings, who were affected with severe Homocystinuria (Cozar 2011). The variant has been also reported in another patient who also carried another potentially pathogenic CBS variant (phase was unknown) (Lorenzini 2018). These data indicate that the variant may be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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