Submissions for variant NC_000015.9:g.(?_91326042)_(91358509_?)del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037522	SCV002115598	likely pathogenic	Bloom syndrome	2021-10-16	criteria provided, single submitter	clinical testing	This variant is a gross deletion of the genomic region encompassing exon(s) 13-22 of the BLM gene, which includes the termination codon. This deletion extends beyond the assayed region for this gene and therefore may encompass additional genes. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to alter mRNA translation or result in a truncated protein product. 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. This variant disrupts the nuclear localization signal (NLS) and the topoisomerase I (TOP1) domain of BLM protein, which are critical for BLM localization to the nucleus and TOP1-mediated RNA:DNA unwinding (PMID: 27657136, 9388480, 10569803, 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. This variant has not been reported in the literature in individuals affected with BLM-related conditions.