ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.881T>C (p.Met294Thr)

gnomAD frequency: 0.00001  dbSNP: rs779346343
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478839 SCV000570768 uncertain significance not provided 2016-06-28 criteria provided, single submitter clinical testing This variant is denoted NBN c.881T>C at the cDNA level, p.Met294Thr (M294T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NBN Met294Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NBN Met294Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the region known for interaction with MTOR, MAPKAP1 and RICTOR (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether NBN Met294Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001036229 SCV001199581 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2022-07-06 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 294 of the NBN protein (p.Met294Thr). This variant is present in population databases (rs779346343, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 421530). 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. 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.
Genome-Nilou Lab RCV001036229 SCV002044763 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446933 SCV002682691 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-16 criteria provided, single submitter clinical testing The p.M294T variant (also known as c.881T>C), located in coding exon 7 of the NBN gene, results from a T to C substitution at nucleotide position 881. The methionine at codon 294 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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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