Submissions for variant NM_001042492.3(NF1):c.4382T>C (p.Met1461Thr)

gnomAD frequency: 0.00001  dbSNP: rs754639587

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000497236	SCV000753634	uncertain significance	Neurofibromatosis, type 1	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1440 of the NF1 protein (p.Met1440Thr). This variant is present in population databases (rs754639587, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 28961165). ClinVar contains an entry for this variant (Variation ID: 431641). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001310356	SCV001500114	uncertain significance	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805117	SCV002051380	uncertain significance	not specified	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4319T>C (p.Met1440Thr) results in a non-conservative amino acid change located in the Ras GTPase-activating domain (IPR001936) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 239966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4319T>C has been reported in the literature with a pathogenicity score of 3 (VUS) in a study of individuals with a clinical diagnosis of Neurofibromatosis Type 1 (example, Bonatti_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000497236	SCV002560415	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329180	SCV002633227	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-01-02	criteria provided, single submitter	clinical testing	The p.M1440T variant (also known as c.4319T>C), located in coding exon 32 of the NF1 gene, results from a T to C substitution at nucleotide position 4319. The methionine at codon 1440 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in an individual with a clinical diagnosis of Neurofibromatosis type 1 (NF1), and classified as a variant of uncertain significance by the authors (Bonatti F et al. Int J Mol Sci, 2017 Sep;18:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Medical Genetics, University of Parma	RCV000497236	SCV000588783	uncertain significance	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing
GeneDx	RCV001310356	SCV002761962	likely pathogenic	not provided	2022-12-09	flagged submission	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 22807134, 25074460, 28961165, 25486365)