Submissions for variant NM_001042492.3(NF1):c.7255_7256del (p.Leu2419fs)

dbSNP: rs1597858459

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819137	SCV000959780	pathogenic	Neurofibromatosis, type 1	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2398Glyfs*2) 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 neurofibromatosis type I (PMID: 12112660, 16786508). ClinVar contains an entry for this variant (Variation ID: 661667). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000819137	SCV001478937	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001546794	SCV001766377	pathogenic	not provided	2023-03-14	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: 12112660, 31766501, 16786508, 31776437, 34233200)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001546794	SCV002049883	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	The NF1 c.7255_7256delCT; p.Leu2419GlyfsTer2 variant, also known as c.7192_7193delCT in transcript NM_000267.3 or as 7190delCT, is reported in the literature in several individuals affected with neurofibromatosis type 1 (Origone 2002, Upadhyaya 2006). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, 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: Origone P et al. Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients. Hum Mutat. 2002 Jul;20(1):74-5. Upadhyaya M et al. The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs). Hum Mutat. 2006 Jul;27(7):716.
Genome-Nilou Lab	RCV000819137	SCV002560561	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
3billion	RCV000819137	SCV002572661	pathogenic	Neurofibromatosis, type 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000661667 / PMID: 12112660). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000819137	SCV002580344	pathogenic	Neurofibromatosis, type 1	2021-08-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003166382	SCV003893861	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-30	criteria provided, single submitter	clinical testing	The c.7192_7193delCT pathogenic mutation, located in coding exon 48 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 7192 to 7193, causing a translational frameshift with a predicted alternate stop codon (p.L2398Gfs*2). This alteration has been identified in multiple individuals with a confirmed or suspected clinical diagnosis of neurofibromatosis type 1 (Origone P et al. Hum Mutat, 2002 Jul;20:74-5; Upadhyaya M et al. Hum Mutat, 2006 Jul;27:716; Pasmant E et al. Eur J Hum Genet, 2015 May;23:596-601; Melloni G et al. Cancers (Basel), 2019 Nov;11; Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This alteration is also referred to as 7190delCT in the literature. 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.
Baylor Genetics	RCV003461256	SCV004199001	pathogenic	Juvenile myelomonocytic leukemia	2022-02-03	criteria provided, single submitter	clinical testing