ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1973T>C (p.Ile658Thr)

dbSNP: rs187379039
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000702507 SCV000831363 uncertain significance Bloom syndrome 2024-04-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 658 of the BLM protein (p.Ile658Thr). 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: 579265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 23129629). 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 RCV002422580 SCV002721636 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-14 criteria provided, single submitter clinical testing The p.I658T variant (also known as c.1973T>C), located in coding exon 7 of the BLM gene, results from a T to C substitution at nucleotide position 1973. The isoleucine at codon 658 is replaced by threonine, an amino acid with similar properties. One yeast-based functional assay showed that p.I658T behaves similarly to wild-type (Mirzaei H et al. Proc Natl Acad Sci U S A 2012 Nov;109(47):19357-62). This amino acid position is well conserved in available vertebrate species. 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.

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