Submissions for variant NM_002485.5(NBN):c.4del (p.Trp2fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389546	SCV001590940	pathogenic	Microcephaly, normal intelligence and immunodeficiency	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2Glyfs*18) 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 (no rsID available, gnomAD 0.003%). 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: 1075847). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002341832	SCV002642393	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The c.4delT variant, located in coding exon 1 of the NBN gene, results from a deletion of one nucleotide at nucleotide position 4, causing a translational frameshift with a predicted alternate stop codon (p.W2Gfs*18). The predicted stop codon occurs within the first 150 nucleotides of theNBN gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). However, the impacted region involves the forkhead-associated domain (FHA) which has been implicated in NBN function (Zhao S et al. Nucleic Acids Res., 2002 Nov;30:4815-22). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003469758	SCV004199653	likely pathogenic	Aplastic anemia	2023-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005040268	SCV005675581	likely pathogenic	Microcephaly, normal intelligence and immunodeficiency; Aplastic anemia; Acute lymphoid leukemia	2024-06-18	criteria provided, single submitter	clinical testing

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