Submissions for variant NM_001042492.3(NF1):c.2054C>G (p.Thr685Ser)

gnomAD frequency: 0.00001  dbSNP: rs876658190

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216178	SCV000273112	uncertain significance	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing	The p.T685S variant (also known as c.2054C>G), located in coding exon 18 of the NF1 gene, results from a C to G substitution at nucleotide position 2054. The threonine at codon 685 is replaced by serine, 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 30,000 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.T685Sremains unclear.
Invitae	RCV000233280	SCV000284402	uncertain significance	Neurofibromatosis, type 1	2023-08-02	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 229779). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 685 of the NF1 protein (p.Thr685Ser).
GeneDx	RCV002222446	SCV002499883	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 25486365)
Genome-Nilou Lab	RCV000233280	SCV002561990	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478783	SCV002785469	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558469	SCV005047592	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-02-12	criteria provided, single submitter	clinical testing	The c.2054C>G (p.T685S) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a C to G substitution at nucleotide position 2054, causing the threonine (T) at amino acid position 685 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.