Submissions for variant NM_001042492.3(NF1):c.7643T>G (p.Ile2548Arg)

gnomAD frequency: 0.00001  dbSNP: rs864622266

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206618	SCV000259905	uncertain significance	Neurofibromatosis, type 1	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2527 of the NF1 protein (p.Ile2527Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 219822). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. 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.
Ambry Genetics	RCV000215851	SCV000274463	uncertain significance	Hereditary cancer-predisposing syndrome	2016-01-14	criteria provided, single submitter	clinical testing	The p.I2548R variant (also known as c.7643T>G), located in coding exon 52 of the NF1 gene, results from a T to G substitution at nucleotide position 7643. The isoleucine at codon 2548 is replaced by arginine, an amino acid with some 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 6503 samples (13006 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.I2548R remains unclear.
GeneDx	RCV001762433	SCV002008360	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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
Genome-Nilou Lab	RCV000206618	SCV002561114	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462371	SCV004198294	uncertain significance	Juvenile myelomonocytic leukemia	2024-02-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558452	SCV005048443	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-19	criteria provided, single submitter	clinical testing	The c.7580T>G (p.I2527R) alteration is located in exon 51 (coding exon 51) of the NF1 gene. This alteration results from a T to G substitution at nucleotide position 7580, causing the isoleucine (I) at amino acid position 2527 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.