Submissions for variant NM_001042492.3(NF1):c.7439A>G (p.His2480Arg)

gnomAD frequency: 0.00001  dbSNP: rs371151718

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217787	SCV000272223	uncertain significance	not specified	2015-03-09	criteria provided, single submitter	clinical testing	The p.His2480Arg in NF1 has not been previously reported in individuals with RAS opathy disorders, but has been identified in 2/66700 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371 151718). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinica l significance of the p.His2480Arg variant is uncertain.
Ambry Genetics	RCV000216591	SCV000275734	uncertain significance	Hereditary cancer-predisposing syndrome	2015-05-14	criteria provided, single submitter	clinical testing	The p.H2480R variant (also known as c.7439A>G andc.7376A>G andp.H2459R), located in coding exon 50 of the NF1 gene, results from an A to G substitution at nucleotide position 7439. The histidine at codon 2480 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1985patients who eitherhad a clinical diagnosis of neurofibromatosis type 1 (NF1)or had some clinical features of NF1 (van Minkelen R et al. Clin Genet. 2014 Apr;85(4):318-27).This variant was previously reported in the SNPDatabase as rs371151718. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles.This variant was not reported in the 1000 Genomes Project population-based cohort. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.H2480Rremains unclear.
Invitae	RCV000693913	SCV000822336	uncertain significance	Neurofibromatosis, type 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2459 of the NF1 protein (p.His2459Arg). This variant is present in population databases (rs371151718, gnomAD 0.003%). This missense change has been observed in individual(s) with neurofibromatosis type 1, Noonan spectrum disorders with cafe au lait spots or Neurofibromatosis-Noonan syndrome (PMID: 23656349, 32107864). ClinVar contains an entry for this variant (Variation ID: 229064). 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 not expected to disrupt NF1 protein function with a negative 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	RCV001778803	SCV002015448	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing	Reported previously as c.7349A>G in an alternate transcript, as a variant of uncertain significance, in a patient with a suspected RASopathy; however, no further clinical or segregation information was provided (Witkowski et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21520333, 23656349, 25486365, 32107864)
Genome-Nilou Lab	RCV000693913	SCV002561080	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500714	SCV002799631	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-02-17	criteria provided, single submitter	clinical testing