ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.1247T>C (p.Met416Thr)

gnomAD frequency: 0.00001  dbSNP: rs863224713
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000198264 SCV000254762 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2023-11-25 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 416 of the NBN protein (p.Met416Thr). This variant is not present in population databases (gnomAD no frequency). 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: 216563). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759886 SCV000889544 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781644 SCV000919855 uncertain significance not specified 2018-11-23 criteria provided, single submitter clinical testing Variant summary: NBN c.1247T>C (p.Met416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246138 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1247T>C in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001010551 SCV001170772 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-14 criteria provided, single submitter clinical testing The p.M416T variant (also known as c.1247T>C), located in coding exon 10 of the NBN gene, results from a T to C substitution at nucleotide position 1247. The methionine at codon 416 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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.
Genome-Nilou Lab RCV000198264 SCV002044680 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002503783 SCV002803826 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2022-05-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV000198264 SCV001460717 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-09-16 no assertion criteria provided clinical testing

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