Submissions for variant NM_001042492.3(NF1):c.1802G>A (p.Arg601Gln)

dbSNP: rs1060500288

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472905	SCV000542055	uncertain significance	Neurofibromatosis, type 1	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the NF1 protein (p.Arg601Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 404478). 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.
GeneDx	RCV000681095	SCV000808550	uncertain significance	not provided	2018-01-25	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.1802G>A at the cDNA level, p.Arg601Gln (R601Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Arg601Gln was not observed in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Luo 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Arg601Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genome-Nilou Lab	RCV000472905	SCV002561944	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411427	SCV002713169	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-11-10	criteria provided, single submitter	clinical testing	The p.R601Q variant (also known as c.1802G>A), located in coding exon 16 of the NF1 gene, results from a G to A substitution at nucleotide position 1802. The arginine at codon 601 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was not observed in 7,051 unselected female breast cancer patients and was observed in 1/11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506093	SCV002816931	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-07-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551508	SCV004722426	uncertain significance	NF1-related disorder	2023-12-20	criteria provided, single submitter	clinical testing	The NF1 c.1802G>A variant is predicted to result in the amino acid substitution p.Arg601Gln. To our knowledge, this variant has not been reported in individuals with NF1-related disorders or in a large population database, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404478/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.