ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.98+1G>T (rs750293380)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410622 SCV000485449 likely pathogenic Bloom syndrome 2015-12-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000410622 SCV000893387 pathogenic Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000410622 SCV000916682 likely pathogenic Bloom syndrome 2018-07-09 criteria provided, single submitter clinical testing Variant summary: BLM c.98+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. These predictions are supported by RT-PCR studies that showed exon 2 skipping, though the data was not available for review (German_2007). The variant allele was found at a frequency of 1.3e-05 in 225466 control chromosomes. c.98+1G>T has been reported in the literature in one individual affected with Bloom Syndrome, which does not allow strong conclusions about variant significance. A different variant at the same location (c.98+1G>A) has also been implicated in Bloom Syndrome. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000410622 SCV000940882 likely pathogenic Bloom syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the BLM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs750293380, ExAC 0.003%). This variant has been observed in an individual affected with clinical features of Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 370200). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). 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.

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