Submissions for variant NM_001042492.3(NF1):c.5189C>G (p.Thr1730Ser)

dbSNP: rs772831692

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222639	SCV000274422	uncertain significance	Hereditary cancer-predisposing syndrome	2015-03-11	criteria provided, single submitter	clinical testing	The p.T1730S variant (also known as c.5189C>G), located in coding exon 37 of the NF1 gene, results from a C to G substitution at nucleotide position 5189. The threonine at codon 1730 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, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.T1730S remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857767	SCV002252599	uncertain significance	Neurofibromatosis, type 1	2024-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1709 of the NF1 protein (p.Thr1709Ser). 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: 230762). 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%. This variant disrupts the p.Thr1709 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35240321). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001857767	SCV002560519	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558497	SCV005048189	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-11-13	criteria provided, single submitter	clinical testing	The c.5126C>G (p.T1709S) alteration is located in exon 36 (coding exon 36) of the NF1 gene. This alteration results from a C to G substitution at nucleotide position 5126, causing the threonine (T) at amino acid position 1709 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.