Submissions for variant NM_001042492.3(NF1):c.2665dup (p.Thr889fs)

dbSNP: rs886041348

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000327872	SCV000329839	pathogenic	not provided	2016-10-06	criteria provided, single submitter	clinical testing	The c.2665dupA variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Sabbagh et al., 2013). The duplication causes a frameshift starting with codon Threonine 889, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Thr889AsnfsX17. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660016	SCV000781957	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660016	SCV001586753	pathogenic	Neurofibromatosis, type 1	2021-11-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280056). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 23913538). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr889Asnfs*17) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).
Genome-Nilou Lab	RCV000660016	SCV002561795	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429207	SCV002743834	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-12-16	criteria provided, single submitter	clinical testing	The c.2665dupA pathogenic mutation, located in coding exon 21 of the NF1 gene, results from a duplication of A at nucleotide position 2665, causing a translational frameshift with a predicted alternate stop codon (p.T889Nfs*17). This alteration was identified in one individual from a cohort of 521 German and Turkish patients with a clinical diagnosis of neurofibromatosis type I as well as one of 565 unrelated French probands with clinical diagnoses or suspicion of NF1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000660016	SCV004039139	pathogenic	Neurofibromatosis, type 1	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2665dupA (p.Thr889AsnfsX17) 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. The variant was absent in 251138 control chromosomes (gnomAD). c.2665dupA has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (e.g., Sabbagh_2013). These data suggest the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 23913538). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.