Submissions for variant NM_002485.5(NBN):c.60del (p.Gly21fs)

gnomAD frequency: 0.00001  dbSNP: rs758708229

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657335	SCV000779067	likely pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000815061	SCV000955504	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly21Alafs*14) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs758708229, gnomAD 0.002%). 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: 545793). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001024899	SCV001186992	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-13	criteria provided, single submitter	clinical testing	The c.60delT pathogenic mutation, located in coding exon 2 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 60, causing a translational frameshift with a predicted alternate stop codon (p.G21Afs*14). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000815061	SCV002045388	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000815061	SCV002548240	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: NBN c.60delT (p.Gly21AlafsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251330 control chromosomes. To our knowledge, no occurrence of c.60delT in individuals affected with Nijmegen Breakage Syndrome has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four laboratories classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003472052	SCV004199627	likely pathogenic	Aplastic anemia	2023-06-28	criteria provided, single submitter	clinical testing