Submissions for variant NM_001042492.3(NF1):c.1019_1020del (p.Ser340fs)

dbSNP: rs1555610903

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659975	SCV000781890	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788498	SCV000927642	likely pathogenic	not provided	2018-04-19	criteria provided, single submitter	clinical testing
Invitae	RCV000659975	SCV000954165	pathogenic	Neurofibromatosis, type 1	2023-10-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser340Cysfs*12) 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 1 (PMID: 9298829, 18546366, 20964122, 31201679, 31370276). This variant is also known as c.1017_c.1018delCT. ClinVar contains an entry for this variant (Variation ID: 547579). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009571	SCV001169672	pathogenic	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
Ambry Genetics	RCV002317911	SCV001169787	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-06-13	criteria provided, single submitter	clinical testing	The c.1019_1020delCT variant, located in coding exon 9 of the NF1 gene, results from a deletion of two nucleotides at nucleotide positions 1019 to 1020, causing a translational frameshift with a predicted alternate stop codon (p.S340Cfs*12). This mutation has been detected in one individual who met NIH diagnostic criteria for NF1 (Upadhyaya M, et al. Hum. Mutat. 1997;10(3):248-50). 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.
Medical Genetics, University of Parma	RCV000659975	SCV001218911	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000788498	SCV001447810	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000659975	SCV001478914	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000788498	SCV001812901	pathogenic	not provided	2021-12-01	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 (Lek 2016); This variant is associated with the following publications: (PMID: 20964122, 9298829, 18546366, 31370276, 31533797, 31776437)
3billion	RCV001775144	SCV002012019	pathogenic	Neurofibromatosis-Noonan syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: 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 (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000547579.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000659975	SCV002561620	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000659975	SCV002579968	pathogenic	Neurofibromatosis, type 1	2022-05-20	criteria provided, single submitter	clinical testing