ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.547G>A (p.Ala183Thr) (rs151070415)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475501 SCV000553127 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 183 of the NBN protein (p.Ala183Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs151070415, ExAC 0.001%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 411786). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000570581 SCV000662690 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586067 SCV000697973 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The NBN c.547G>A (p.Ala183Thr) variant indicated to be located at the last amino position of the BRCT domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121276, which does not exceed the estimated maximal expected allele frequency for a pathogenic NBN variant of 1/400. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance."
Color RCV000570581 SCV000909720 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing

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