Submissions for variant NM_001042492.3(NF1):c.6955G>A (p.Ala2319Thr)

dbSNP: rs786203881

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167378	SCV000218232	uncertain significance	Hereditary cancer-predisposing syndrome	2014-12-23	criteria provided, single submitter	clinical testing	Thep.A2319Tvariant (also known as c.6955G>A), located in coding exon 47 of theNF1gene, results from a G to A substitution at nucleotide position 6955. The alanine at codon 2319 is replaced by threonine, 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 30000 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.A2319Tremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548645	SCV000628743	uncertain significance	Neurofibromatosis, type 1	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2298 of the NF1 protein (p.Ala2298Thr). 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: 187632). 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 with a positive 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.
Genome-Nilou Lab	RCV000548645	SCV002561019	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558417	SCV005048347	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-06-24	criteria provided, single submitter	clinical testing	The c.6892G>A (p.A2298T) alteration is located in exon 46 (coding exon 46) of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 6892, causing the alanine (A) at amino acid position 2298 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005016507	SCV005639949	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-06-12	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000548645	SCV005685139	uncertain significance	Neurofibromatosis, type 1	2024-06-03	criteria provided, single submitter	clinical testing	The NF1 c.6955G>A (p.Ala2319Thr) variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a variant of uncertain significance by 2 submitters (Variation ID: 187632). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on NF1 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.