Submissions for variant NM_001042492.3(NF1):c.4372GAA[1] (p.Glu1459del)

dbSNP: rs267606607

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000544772	SCV000628588	pathogenic	Neurofibromatosis, type 1	2023-07-08	criteria provided, single submitter	clinical testing	This variant, c.4312_4314del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Glu1438del), 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 individual(s) with classic neurofibromatosis type 1 and neurofibromatosis-Noonan syndrome (NFNS) (PMID: 12707950, 15060124, 18546366, 19863548). In at least one individual the variant was observed to be de novo. This variant is also known as 4312 del GAAdE1438. ClinVar contains an entry for this variant (Variation ID: 364). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000544772	SCV001479104	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000544772	SCV002560047	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326657	SCV002633205	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-13	criteria provided, single submitter	clinical testing	The c.4312_4314delGAA variant (also known as p.E1438del) is located in coding exon 32 of the NF1 gene. This variant results from an in-frame GAA deletion at nucleotide positions 4312 to 4314. This results in the in-frame deletion of a glutamic acid at codon 1438. This alteration has been detected in individuals meeting diagnostic criteria for neurofibromatosis type 1 (NF1) (Mattocks C et al. J Med Genet, 2004 Apr;41:e48; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data) and in several individuals with clinically definite or suspected NF1 diagnoses (Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60; Baralle D et al. Am. J. Med. Genet. A, 2003 May;119A:1-8; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This alteration was reported as a de novo occurrence in an individual with multiple spinal ganglioneuromas and cafe-au-lait spots but who did not have other NF1 features (Bacci C et al. Clin. Genet., 2010 Mar;77:293-7). Of note, this variant is also designated as 4312delGAA and ΔE1438 in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). As such, this alteration is classified as likely pathogenic.
GeneDx	RCV003156210	SCV003845687	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in multiple unrelated patients with suspected or clinically diagnosed neurofibromatosis type 1 or NF1-Noonan syndrome referred for genetic testing at GeneDx and in published literature (Baralle et al., 2003; Mattocks et al., 2004; De Luca et al., 2005; Pros et al., 2008; Xu et al., 2014; Kang et al., 2020); Identified as a de novo variant with confirmed parentage in an individual referred for genetic testing at GeneDx and as apparently de novo in an individual in the published literature, both with personal histories consistent with pathogenic variants in this gene (Bacci et al., 2010); This variant is associated with the following publications: (PMID: 15060124, 12707950, 16380919, 18546366, 24789688, 31487937, 23047742, 19863548, 23913538, 31776437, 12807981)
PreventionGenetics, part of Exact Sciences	RCV003415600	SCV004113248	pathogenic	NF1-related condition	2022-10-10	criteria provided, single submitter	clinical testing	The NF1 c.4375_4377delGAA variant is predicted to result in an in-frame deletion (p.Glu1459del). This variant is also described as c.4312_4314delGAA, and has been reported to be causative for neurofibromatosis (Mattocks et al. 2004. PubMed ID: 15060124; Bacci et al. 2010. PubMed ID: 19863548) and has also been reported in a patient with Neurofibromatosis-Noonan syndrome (NFNS) (Baralle et al. 2003. PubMed ID: 12707950). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/364/). Based on this evidence, we interpret this variant as pathogenic.
Baylor Genetics	RCV003466771	SCV004190805	pathogenic	Juvenile myelomonocytic leukemia	2022-07-01	criteria provided, single submitter	clinical testing
OMIM	RCV000000394	SCV000020538	pathogenic	Neurofibromatosis-Noonan syndrome	2003-05-15	no assertion criteria provided	literature only