Submissions for variant NM_002485.5(NBN):c.1030C>T (p.Gln344Ter)

gnomAD frequency: 0.00001  dbSNP: rs767215758

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220210	SCV000279456	pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing	Nonsense 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 a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25677497)
Counsyl	RCV000170448	SCV000486381	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency	2016-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000170448	SCV000553057	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln344*) 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 (rs767215758, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 25677497). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 190229). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000446931	SCV000662663	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	The p.Q344* pathogenic mutation (also known as c.1030C>T), located in coding exon 9 of the NBN gene, results from a C to T substitution at nucleotide position 1030. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in trans with a second NBN mutation in an individual with Nijmegen breakage syndrome (Patel JP et al. J Clin Immunol, 2015 Feb;35:227-33). In addition to the clinical data presented in the literature, 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.
Fulgent Genetics, Fulgent Genetics	RCV000763607	SCV000894453	pathogenic	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000220210	SCV002018224	pathogenic	not provided	2019-02-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000170448	SCV002045345	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	RCV000170448	SCV002548239	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2022-05-27	criteria provided, single submitter	clinical testing	Variant summary: NBN c.1030C>T (p.Gln344X) 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 251386 control chromosomes (gnomAD). The variant, c.1030C>T, has been reported in the literature in the compound heterozygous state in an individual affected with Nijmegen Breakage Syndrome (Patel_2015). Peripheral blood lymphocytes from this patient showed no detectable nibrin protein by immunoblot and were radiosensitive compared to normal controls (Patel_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight laboratories classified the variant as pathogenic, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474919	SCV004199655	pathogenic	Aplastic anemia	2024-02-19	criteria provided, single submitter	clinical testing
Innovations Lab, Hyderabad, Tata Consultancy Services Ltd	RCV000170448	SCV000196641	pathogenic	Microcephaly, normal intelligence and immunodeficiency		no assertion criteria provided	research	Exome sequencing of DNA from an infant and his parents was performed. Genomic analysis revealed deleterious variants in the NBN gene. Confirmatory testing included Sanger sequencing and immunoblotting and radiosensitivity testing of patient lymphocytes.
Natera, Inc.	RCV000170448	SCV002078606	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2020-12-16	no assertion criteria provided	clinical testing