ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.2215C>G (p.Leu739Val) (rs370058152)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160797 SCV000215461 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160797 SCV000690700 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764782 SCV000895926 uncertain significance Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000590749 SCV000211462 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing This variant is denoted NBN c.2215C>G at the cDNA level, p.Leu739Val (L739V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. NBN Leu739Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with ATM (Damiola 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NBN Leu739Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590749 SCV000697964 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing Variant summary: The c.2215C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 3/115508 control chromosomes at a frequency of 0.000026, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0025). In addition, multiple clinical laboratories classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000168129 SCV000218788 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 739 of the NBN protein (p.Leu739Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs370058152, ExAC 0.005%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 182730). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics RCV000168129 SCV000838295 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing

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