ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1666G>A (p.Val556Met) (rs771567358)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000636781 SCV000758222 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 556 of the NBN protein (p.Val556Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs771567358, ExAC 0.03%). This variant has not been reported in the literature in individuals with NBN-related disease. 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, but 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.
Integrated Genetics/Laboratory Corporation of America RCV000780527 SCV000917859 uncertain significance not specified 2018-07-02 criteria provided, single submitter clinical testing Variant summary: NBN c.1666G>A (p.Val556Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245966 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.1666G>A 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.

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