Submissions for variant NM_001042492.3(NF1):c.7663A>G (p.Lys2555Glu)

dbSNP: rs786203792

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167247	SCV000218087	uncertain significance	Hereditary cancer-predisposing syndrome	2014-12-24	criteria provided, single submitter	clinical testing	The p.K2555E variant (also known as c.7663A>G and c.7600A>G and p.K2534E), located in coding exon 52 of the NF1 gene, results from an A to G substitution at nucleotide position 7663. The lysine at codon 2555 is replaced by glutamic acid, an amino acid with 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 0.003% (greater than 30000alleles 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.K2555Eremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001295743	SCV001484688	uncertain significance	Neurofibromatosis, type 1	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2534 of the NF1 protein (p.Lys2534Glu). 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: 187512). 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.
Genome-Nilou Lab	RCV001295743	SCV002561116	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558412	SCV003745353	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-06-29	criteria provided, single submitter	clinical testing	The c.7600A>G (p.K2534E) alteration is located in exon 51 (coding exon 51) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 7600, causing the lysine (K) at amino acid position 2534 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.