ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3751G>C (p.Glu1251Gln) (rs587779888)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115312 SCV000149221 likely pathogenic not provided 2013-10-03 criteria provided, single submitter clinical testing This variant is denoted c.3751G>C at the cDNA level or p.Glu1251Gln (E1251Q) at the protein level. BLM E1251Q results in the semi-conservative replacement of a negatively charged Glutaminc Acid codon (GAA) with a neutral Glutamine codon (CAA) at amino acid position 1251 in exon 19 of the BLM gene. This variant is in a highly conserved residue within the HDRC (Helicase and Rnase D C-terminal) domain. It has not been published as a mutation to our knowledge but is predictedto reduce or abolish the natural cannonical splice donor site of exon 19. In silico models are not consistent in their predictions whether or not this variant has an effect on protein structure or function. Additionally, the NHLBI ESP Exome Variant Server reports that this variant was not observed in approximately 6500 individuals of European American and African American descent, suggesting that it is not a common benign variant in these populations.Therefore, based on the currently available information, we consider E1251Q to be a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HEREDICANCER panel(s).
Invitae RCV000699350 SCV000828056 uncertain significance Bloom syndrome 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1251 of the BLM protein (p.Glu1251Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant also falls at the last nucleotide of exon 19 of the BLM coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs587779888, ExAC 0.003%) but has not been reported in the literature in individuals with a BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127504). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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