ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 401 of the NBN protein (p.Pro401Arg). This variant is present in population databases (rs104895033, gnomAD 0.07%). 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: 127010). 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. 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.

The p.P401R variant (also known as c.1202C>G), located in coding exon 10 of the NBN gene, results from a C to G substitution at nucleotide position 1202. The proline at codon 401 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly 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.

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in several individuals with primary antibody deficiency syndromes (PMID: 20805886); This variant is associated with the following publications: (PMID: 24894818, 36346689, 20805886)

The NBN p.Pro401Arg variant was identified in 2 of 876 proband chromosomes (frequency: 0.002) from individuals or families of Swedish descent with immunoglobulin A deficiency (IgAD) or common variable immunodeficiency (CVID) and was not identified in 1892 control chromosomes from healthy individuals (Offer 2010). The variant was also identified in dbSNP (ID: rs104895033) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color, and Counsyl). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 17 of 245910 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017) in the following populations: Other in 1 of 5472 chromosomes (freq: 0.0002), European Non-Finnish in 1 of 111484 chromosomes (freq: 0.000009), and European Finnish in 15 of 22284 chromosomes (freq: 0.0007), while it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Pro401 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.