ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.644G>A (p.Arg215Gln) (rs61753718)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130586 SCV000185459 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587953 SCV000279506 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted NBN c.644G>A at the cDNA level, p.Arg215Gln (R215Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. NBN Arg215Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. NBN Arg215Gln occurs at a position that is not conserved and is located in the region of interaction with SP100 and is involved in directing the relative orientation of both BRCT domains (di Masi 2008, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NBN Arg215Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000461583 SCV000553071 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 215 of the NBN protein (p.Arg215Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs61753718, ExAC 0.006%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 141888). 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: "Possibly 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.
Color RCV000130586 SCV000685806 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587953 SCV000697977 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The NBN c.644G>A (p.Arg215Gln) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120184 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025). 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. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000461583 SCV000799005 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-04-03 criteria provided, single submitter clinical testing

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