Submissions for variant NM_001042492.3(NF1):c.7213A>G (p.Ile2405Val)

gnomAD frequency: 0.00001  dbSNP: rs565708398

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165705	SCV000216446	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-08	criteria provided, single submitter	clinical testing	The p.I2405V variant (also known as c.7213A>G), located in coding exon 49 of the NF1 gene, results from an A to G substitution at nucleotide position 7213. The isoleucine at codon 2405 is replaced by valine, 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 6501 samples (13002 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55000 alleles tested) in our clinical cohort.<span style="background-color:initial"><span style="background-color:initial">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. <span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">p.I2405V<span style="background-color:initial">remains unclear.
Invitae	RCV000196434	SCV000254509	uncertain significance	Neurofibromatosis, type 1	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2384 of the NF1 protein (p.Ile2384Val). This variant is present in population databases (rs565708398, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 186162). 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.
Fulgent Genetics, Fulgent Genetics	RCV000515215	SCV000611413	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2017-05-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000196434	SCV000839161	uncertain significance	Neurofibromatosis, type 1	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001548376	SCV001768275	likely benign	not provided	2021-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001818383	SCV002071952	uncertain significance	not specified	2021-10-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.7150A>G, in exon 48 that results in an amino acid change, p.Ile2384Val. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the Latino/Admixed American subpopulation (dbSNP rs565708398).The p.Ile2384Val change affects a poorly conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. The p.Ile2384Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequences change does not appear to have been previously described in individuals with NF1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile2384Val change remains unknown at this time.
Sema4, Sema4	RCV000165705	SCV002530190	likely benign	Hereditary cancer-predisposing syndrome	2021-02-05	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV001548376	SCV003815861	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162703	SCV003895173	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001548376	SCV004565291	likely benign	not provided	2023-03-27	criteria provided, single submitter	clinical testing