ClinVar Miner

Submissions for variant NM_002485.5(NBN):c.1177T>C (p.Phe393Leu)

gnomAD frequency: 0.00001  dbSNP: rs941732827
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468237 SCV000553040 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 393 of the NBN protein (p.Phe393Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 411739). 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 leucine 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.
Ambry Genetics RCV000570523 SCV000662664 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-17 criteria provided, single submitter clinical testing The p.F393L variant (also known as c.1177T>C), located in coding exon 10 of the NBN gene, results from a T to C substitution at nucleotide position 1177. The phenylalanine at codon 393 is replaced by leucine, an amino acid with highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194317 SCV001363752 uncertain significance not specified 2019-01-07 criteria provided, single submitter clinical testing Variant summary: NBN c.1177T>C (p.Phe393Leu) 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 allele was found at a frequency of 3.2e-05 in 30914 control chromosomes. 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.1177T>C in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV000468237 SCV002045933 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2021-11-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800687 SCV002046491 uncertain significance not provided 2020-12-10 criteria provided, single submitter clinical testing
GeneDx RCV001800687 SCV002599692 uncertain significance not provided 2023-05-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28539123)
Natera, Inc. RCV000468237 SCV001457041 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2020-04-14 no assertion criteria provided clinical testing

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