Submissions for variant NM_001042492.3(NF1):c.3639_3641del (p.Met1215del)

dbSNP: rs1060500276

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467306	SCV000542040	pathogenic	Neurofibromatosis, type 1	2024-01-08	criteria provided, single submitter	clinical testing	This variant, c.3639_3641del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Met1215del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 16835897, 18546366, 26635368). This variant is also known as 3643delATG. ClinVar contains an entry for this variant (Variation ID: 404465). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects NF1 function (PMID: 26635368). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000467306	SCV001479234	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001562547	SCV001785327	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with Neurofibromatosis type 1 (Lee 2006, Pros 2008, Cannon 2018, Hirata 2016); In silico analysis supports a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10712197, 16835897, 26635368, 29415745, 18546366, 25486365, 22807134)
Genome-Nilou Lab	RCV000467306	SCV002559976	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000467306	SCV002567799	pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002451072	SCV002613728	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-06-02	criteria provided, single submitter	clinical testing	The c.3639_3641delAAT pathogenic mutation (also known as p.M1215del) is located in coding exon 27 of the NF1 gene. This pathogenic mutation results from an in-frame AAT deletion at nucleotide positions 3639 to 3641. This results in the in-frame deletion of a methionine at codon 1215. This alteration has been reported in several individuals affected with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Lee MJ et al. Hum Mutat, 2006 Aug;27:832; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Hirata Y et al. J Biol Chem, 2016 Feb;291:3124-34). Functional studies have also demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1 (Hirata Y et al. J Biol Chem, 2016 Feb;291:3124-34; Dunzendorfer-Matt T et al. Proc Natl Acad Sci U S A, 2016 07;113:7497-502). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV004787707	SCV005400699	pathogenic	Neurofibromatosis-Noonan syndrome		criteria provided, single submitter	clinical testing	The observed missense variant c.3639_3641del(p.Met1215del) in NF1 gene has been reported previously in heterozygous state in multiple individuals with neurofibromatosis type 1 (Cannon A, et al., 2018, Dunzendorfer-Matt T, et al., 2016). Experimental studies have demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1, which functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product (Hirata Y, et al., 2016). The c.3639_3641del (p.Met1215del) variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This p.Met1215del causes deletion of amino acid Methionine at position 1215. For these reasons, this variant has been classified as Pathogenic.