Submissions for variant NM_002485.5(NBN):c.37+6G>C

dbSNP: rs540868733

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231974	SCV000287470	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2024-05-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the NBN gene. It does not directly change the encoded amino acid sequence of the NBN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs540868733, gnomAD 0.04%). 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: 239196). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis provides insufficient evidence to determine the effect of this variant on NBN splicing (Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590289	SCV000697967	uncertain significance	not provided	2017-08-16	criteria provided, single submitter	clinical testing	Variant summary: The NBN c.37+6G>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. Additionally, ESE finder predicts the creation of SF2/ASF and SRp55 binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 2/112342 control chromosomes at a frequency of 0.0000178, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; 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 is classified as a variant of uncertain significance (VUS).
Counsyl	RCV000231974	SCV000791592	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2017-05-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000590289	SCV001764296	likely benign	not provided	2020-05-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000231974	SCV002046002	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004017531	SCV004849160	uncertain significance	Hereditary cancer-predisposing syndrome	2014-11-25	criteria provided, single submitter	clinical testing	The c.37+6G>C intronic alteration consists of a G to C substitution nucleotides after coding exon 1 in the NBN gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000231974	SCV001457057	uncertain significance	Microcephaly, normal intelligence and immunodeficiency	2020-01-24	no assertion criteria provided	clinical testing