ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.4000_4004del (p.Arg1334fs) (rs1057516261)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412153 SCV000485373 likely pathogenic Bloom syndrome 2015-11-24 criteria provided, single submitter clinical testing
Invitae RCV000412153 SCV000623327 likely pathogenic Bloom syndrome 2018-08-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BLM (p.Arg1334Glufs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid residues 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 a BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 370136). This truncating variant affects amino acid residues 1334-1349, which constitute the nuclear localization signal (NLS) of the BLM protein (PMID: 9388480) and are required for BLM interaction with topoisomerase I (TOP1) (PMID: 27657136). These residues have been shown in experimental studies to be critical for BLM localization to the nucleus (PMID: 9388480, 10569803, 27657136) and TOP1-mediated RNA:DNA unwinding (PMID: 27657136). 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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