ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1544dup (p.Asn515fs) (rs367543043)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000034890 SCV000623244 pathogenic Bloom syndrome 2018-06-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn515Lysfs*2) in the BLM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in the literature in individuals affected with Bloom syndrome (PMID: 7585968, 17407155). ClinVar contains an entry for this variant (Variation ID: 42064). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000034890 SCV000918658 pathogenic Bloom syndrome 2018-11-12 criteria provided, single submitter clinical testing Variant summary: BLM c.1544dupA (p.Asn515LysfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1642C>T, p.Gln548X; c.2207_2212delinsTAGATTC, p.Tyr736fsX5). The variant was absent in 245606 control chromosomes (gnomAD). c.1544dupA has been reported in the literature in multiple individuals affected with Bloom Syndrome and indicated to be a Japanese founder mutation (Ellis_1995, German_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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