ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3956del (p.Ile1319fs) (rs1555425080)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669899 SCV000794698 likely pathogenic Bloom syndrome 2017-10-13 criteria provided, single submitter clinical testing
Invitae RCV000669899 SCV001219727 likely pathogenic Bloom syndrome 2019-09-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BLM gene (p.Ile1319Asnfs*87). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acids of the BLM protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 554289). This variant disrupts the nuclear localization signal (NLS) and topoisomerase I (TOP1) domains of the BLM protein, which are critical for BLM localization to the nucleus (PMID: 9388480, 10569803, 27657136) and TOP1-mediated RNA:DNA unwinding (PMID: 27657136). While functional studies have not been performed to directly test the effect of this variant on BLM protein function, this suggests that disruption of this region of the protein is causative of disease. 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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