Submissions for variant NM_001042492.3(NF1):c.3447G>A (p.Met1149Ile)

dbSNP: rs1064794277

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485269	SCV000568606	likely pathogenic	not provided	2018-01-24	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.3447G>A at the cDNA level, p.Met1149Ile (M1149I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed as a de novo finding in one individual with a clinical diagnosis of Neurofibromatosis Type 1 and was not identified in greater than 200 normal chromosomes evaluated (Griffiths 2007). NF1 Met1149Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. NF1 Met1149Ile occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider NF1 Met1149Ile to be a likely pathogenic variant.
Invitae	RCV000632422	SCV000753602	pathogenic	Neurofibromatosis, type 1	2019-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. A different variant (c.3447G>T) giving rise to the same protein effect observed here (p.Met1149Ile) has been determined to be pathogenic (Invitae), indicating that this residue may be critical for protein function.. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with neurofibromatosis type 1, being found to be de novo in one case (PMID: 16944272, 27322474). ClinVar contains an entry for this variant (Variation ID: 420079). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1149 of the NF1 protein (p.Met1149Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000632422	SCV000781985	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genomics Laboratory, Department of Genetics UAB	RCV000632422	SCV000999179	pathogenic	Neurofibromatosis, type 1	2019-06-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000632422	SCV002559959	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing