Submissions for variant NM_001042492.3(NF1):c.6462dup (p.Glu2155fs)

dbSNP: rs1135402888

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497056	SCV000628714	pathogenic	Neurofibromatosis, type 1	2024-03-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2134Argfs*14) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of neurofibromatosis type-1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 431673). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000497056	SCV000782074	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356815	SCV001187363	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-06-24	criteria provided, single submitter	clinical testing	The c.6399dupA pathogenic mutation, located in coding exon 42 of the NF1 gene, results from a duplication of A at nucleotide position 6399, causing a translational frameshift with a predicted alternate stop codon (p.E2134Rfs*14). This alteration was reported in a cohort of Italian neurofibromatosis type 1 (NF1) patients (Bonatti F et al. Int J Mol Sci. 2017 Sep;18:). 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.
Genome-Nilou Lab	RCV000497056	SCV002560184	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003327407	SCV004034864	pathogenic	not provided	2023-03-09	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 (gnomAD); This variant is associated with the following publications: (PMID: 23913538, 28961165, 10712197)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003327407	SCV005877392	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	The NF1 c.6462dup; p.Glu2155ArgfsTer14 variant (rs1135402888, ClinVar Variation ID: 431673), also known as c.6399dupA for NM_000267.3, is reported in the literature in an individual affected with neurofibromatosis (Bonatti 2017). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bonatti F et al. Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I. Int J Mol Sci. 2017 Sep 29;18(10):2071. PMID: 28961165.
Medical Genetics, University of Parma	RCV000497056	SCV000588818	pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing