Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000811037 | SCV000951282 | pathogenic | Bloom syndrome | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 407 of the BLM protein (p.Arg407Thr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. 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: 654963). 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). Studies have shown that this missense change results in skipping of exon 6 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002363095 | SCV002659540 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-06-11 | criteria provided, single submitter | clinical testing | The p.R407T variant (also known as c.1220G>C), located in coding exon 5 of the BLM gene, results from a G to C substitution at nucleotide position 1220. This change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. In addition to the potential splicing impact, this alteration changes the arginine at codon 407 to threonine, an amino acid with similar properties. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, and is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Natera, |
RCV000811037 | SCV002090016 | uncertain significance | Bloom syndrome | 2020-09-14 | no assertion criteria provided | clinical testing |