Submissions for variant NM_001042492.3(NF1):c.3295A>G (p.Lys1099Glu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002290901	SCV002578314	likely pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365, 2121369)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003097740	SCV003442620	likely pathogenic	Neurofibromatosis, type 1	2022-12-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1708593). This missense change has been observed in individual(s) with neurofibromatosis type I (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1099 of the NF1 protein (p.Lys1099Glu).
Ambry Genetics	RCV004990766	SCV005454534	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-12-03	criteria provided, single submitter	clinical testing	The p.K1099E variant (also known as c.3295A>G), located in coding exon 25 of the NF1 gene, results from an A to G substitution at nucleotide position 3295. The lysine at codon 1099 is replaced by glutamic acid, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with neurofibromatosis type 1 (NF1); in at least one individual, it was determined to be de novo (external communication; van Minkelen R, et al. Clin. Genet. 2014;85(4):318-27; Xu W, et al. Int. J. Mol. Med. 2014;34(1):53-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.