ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2193+1_2193+9del

dbSNP: rs1060500652
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000469408 SCV000543397 pathogenic Bloom syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 9 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 405328). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000469408 SCV000694476 likely pathogenic Bloom syndrome 2016-08-26 criteria provided, single submitter clinical testing Variant summary: The BLM c.2193+1_2193+9delGTAAGTTAT variant involves the deletion of 9 intronic nucleotides including the highly conserved nucleotides at the +1 and +2 positions. One in silico tool predicts a damaging outcome for this variant and 5/5 in silico splicing prediction tools via Alamut predict the complete loss of a canonical splice acceptor site. This variant is absent in 120322 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, due to the potential impact of this variant on splicing, it is classified as likely pathogenic.
Counsyl RCV000469408 SCV000790435 likely pathogenic Bloom syndrome 2017-03-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV002429478 SCV002728646 likely pathogenic Hereditary cancer-predisposing syndrome 2023-12-07 criteria provided, single submitter clinical testing The c.2193+1_2193+9delGTAAGTTAT intronic variant results from a deletion of 9 nucleotides after coding exon 8 of the BLM gene. The deleted region includes the canonical splice donor site which is highly conserved. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
GeneDx RCV003441865 SCV004170364 likely pathogenic not provided 2023-10-08 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17407155)
Baylor Genetics RCV000469408 SCV004210858 pathogenic Bloom syndrome 2023-11-15 criteria provided, single submitter clinical testing
Natera, Inc. RCV000469408 SCV002088038 likely pathogenic Bloom syndrome 2017-11-07 no assertion criteria provided clinical testing

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