ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2452C>T (p.Arg818Cys)

dbSNP: rs1279814185
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000554341 SCV000623270 uncertain significance Bloom syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 818 of the BLM protein (p.Arg818Cys). This variant is present in population databases (no rsID available, 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: 454104). 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 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 RCV001015589 SCV001176438 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-04 criteria provided, single submitter clinical testing The p.R818C variant (also known as c.2452C>T), located in coding exon 11 of the BLM gene, results from a C to T substitution at nucleotide position 2452. The arginine at codon 818 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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.
GeneDx RCV001755776 SCV001997390 uncertain significance not provided 2020-01-23 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001755776 SCV005624252 uncertain significance not provided 2024-06-18 criteria provided, single submitter clinical testing The BLM c.2452C>T (p.Arg818Cys) variant has not been reported in individuals with BLM-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/251464 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000554341 SCV005689324 uncertain significance Bloom syndrome 2024-08-09 criteria provided, single submitter clinical testing The BLM c.2452C>T (p.Arg818Cys) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Natera, Inc. RCV000554341 SCV002088070 uncertain significance Bloom syndrome 2019-01-06 no assertion criteria provided clinical testing

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