Submissions for variant NM_001042492.3(NF1):c.4832G>A (p.Arg1611Gln)

dbSNP: rs876659197

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223634	SCV000275378	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-18	criteria provided, single submitter	clinical testing	The p.R1611Q variant (also known as c.4832G>A), located in coding exon 36 of the NF1 gene, results from a G to A substitution at nucleotide position 4832. The arginine at codon 1611 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000 alleles tested) in our clinical cohort.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 for this variant is limited at this time, the clinical significance of p.R1611Qremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812956	SCV000953286	likely pathogenic	Neurofibromatosis, type 1	2024-04-01	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 1590 of the NF1 protein (p.Arg1590Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 231506). 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%. This variant disrupts the p.Arg1590 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9298829, 27322474, 29673180; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001762486	SCV002008891	uncertain significance	not provided	2022-11-14	criteria provided, single submitter	clinical testing	Observed in at least one patient from a cohort of individuals with hereditary breast cancer (Momozawa et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30287823)
Genome-Nilou Lab	RCV000812956	SCV002560474	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462465	SCV004198234	uncertain significance	Juvenile myelomonocytic leukemia	2023-12-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001762486	SCV004222173	uncertain significance	not provided	2012-04-10	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (NF1) (PMID: 29673180 (2018), 9298829 (1997)) and breast cancer (PMID: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NF1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV004558516	SCV005048154	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-07-26	criteria provided, single submitter	clinical testing	The c.4769G>A (p.R1590Q) alteration is located in exon 35 (coding exon 35) of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 4769, causing the arginine (R) at amino acid position 1590 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.