Submissions for variant NM_001042492.3(NF1):c.234T>A (p.Asn78Lys)

dbSNP: rs876658354

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219194	SCV000273459	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-16	criteria provided, single submitter	clinical testing	The p.N78K variant (also known as c.234T>A), located in coding exon 3 of the NF1 gene, results from a T to A substitution at nucleotide position 234. The asparagine at codon 78 is replaced by lysine, 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 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.N78K remains unclear.
Invitae	RCV000227890	SCV000284409	uncertain significance	Neurofibromatosis, type 1	2022-12-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 230049). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 78 of the NF1 protein (p.Asn78Lys).
GeneDx	RCV001753656	SCV002005336	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	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
Genome-Nilou Lab	RCV000227890	SCV002561425	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494585	SCV002785303	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-08-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558481	SCV005047622	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-01-31	criteria provided, single submitter	clinical testing	The c.234T>A (p.N78K) alteration is located in exon 3 (coding exon 3) of the NF1 gene. This alteration results from a T to A substitution at nucleotide position 234, causing the asparagine (N) at amino acid position 78 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.