Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000795273 | SCV000934722 | uncertain significance | Bloom syndrome | 2023-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1359 of the BLM protein (p.Gly1359Glu). This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 641919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002325511 | SCV002626478 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing | The c.4076G>A variant (also known as p.G1359E), located in coding exon 20 of the BLM gene, results from a G to A substitution at nucleotide position 4076. The amino acid change results in glycine to glutamic acid at codon 1359, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, internal RNA studies did not detect abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Natera, |
RCV000795273 | SCV002090646 | uncertain significance | Bloom syndrome | 2018-11-11 | no assertion criteria provided | clinical testing |