ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2489C>T (p.Thr830Met)

gnomAD frequency: 0.00001  dbSNP: rs759545027
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001822363 SCV002066647 uncertain significance not specified 2020-10-29 criteria provided, single submitter clinical testing DNA sequence analysis of the BLM gene demonstrated a sequence change, c.2489C>T, in exon 12 that results in an amino acid change, p.Thr830Met. This sequence change does not appear to have been previously described in patients with BLM-related disorders. This sequence change has been described in two individuals in the gnomAD population database (dbSNP rs759545027). The p.Thr830Met change affects highly conserved amino acid residue located in the helicase domain of the BLM protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr830Met substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr830Met change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001869747 SCV002188679 uncertain significance Bloom syndrome 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 830 of the BLM protein (p.Thr830Met). This variant is present in population databases (rs759545027, gnomAD 0.003%). 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: 1337765). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. 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 RCV002425090 SCV002742236 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-25 criteria provided, single submitter clinical testing The p.T830M variant (also known as c.2489C>T), located in coding exon 11 of the BLM gene, results from a C to T substitution at nucleotide position 2489. The threonine at codon 830 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Breakthrough Genomics, Breakthrough Genomics RCV004692755 SCV005194009 uncertain significance not provided criteria provided, single submitter not provided

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