ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.1337C>A (p.Thr446Lys)

gnomAD frequency: 0.00001  dbSNP: rs1447973805
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001208525 SCV001379918 uncertain significance Bloom syndrome 2021-09-04 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with BLM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 446 of the BLM protein (p.Thr446Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine.
Ambry Genetics RCV003163580 SCV003894637 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-26 criteria provided, single submitter clinical testing The p.T446K variant (also known as c.1337C>A), located in coding exon 6 of the BLM gene, results from a C to A substitution at nucleotide position 1337. The threonine at codon 446 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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