Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001031120 | SCV001194426 | likely pathogenic | Bloom syndrome | 2019-09-15 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 20-22 of the BLM gene. The 5' boundary is likely confined to intron 19. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. A similar deletion of exons 4-8 has been observed to be homozygous in an individual affected with Bloom syndrome (PMID: 17407155). This deletion 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. |