ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2098C>T (p.Gln700Ter) (rs367543028)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000034893 SCV000485410 pathogenic Bloom syndrome 2015-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000317685 SCV000329113 pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing The Q700X pathogenic variant in the BLM gene has been reported previously in multiple individuals with Bloom syndrome in the homozygous state, as well as in the heterozygous state in the presence of a second BLM variant (German et al., 2007). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q700X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q700X as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000034893 SCV000916688 pathogenic Bloom syndrome 2018-09-14 criteria provided, single submitter clinical testing Variant summary: BLM c.2098C>T (p.Gln700X) 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 (e.g. c.2207_2212delinsTAGATTC (p.Tyr736fsX5) and c.2695C>T (p.Arg899X)). The variant allele was found at a frequency of 1.1e-05 in 277168 control chromosomes (gnomAD). c.2098C>T has been reported in the literature, in homozygosity or compound heterozygosity, in multiple individuals affected with Bloom Syndrome (German_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the variant impact. The most pronounced variant effect in homozygous individuals resulted in <20% mRNA amount compared to normal, based on Northern blot analyses (German_2007). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000034893 SCV000543350 pathogenic Bloom syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln700*) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs367543028, ExAC 0.003%). This variant has been reported in the literature as homozygous, or compound heterozygous with another pathogenic BLM variant, in several individuals with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42067). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.

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