ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000412153 SCV000623327 likely pathogenic Bloom syndrome 2020-10-12 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.
Ambry Genetics RCV001021637 SCV001183277 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing The c.4000_4004delAGGAA variant, located in coding exon 20 of the BLM gene, results from a deletion of 5 nucleotides at nucleotide positions 4000 to 4004, causing a translational frameshift with a predicted alternate stop codon (p.R1334Efs*11). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of BLM, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 84 amino acids of the protein. This alteration changes amino acid residues within the nuclear localization signal of the BLM protein (Kaneko H et al. Biochem Biophys Res Commun. 1997 Nov 17;240(2):348-53, Gharibyan V and Youssoufian H. Mol Carcinog. 1999 Dec;26(4):261-73) and amino acid residues involved in the interaction of BLM with topoisomerase I (TOP1) (Tangeman L et al. Genes (Basel). 2016 Sep 21;7(9)). However, the exact functional impact of this alteration on BLM activity is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Counsyl RCV000412153 SCV000485373 likely pathogenic Bloom syndrome 2015-11-24 no assertion criteria provided clinical testing

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