Submissions for variant NM_001042492.3(NF1):c.3187T>C (p.Cys1063Arg)

dbSNP: rs776079267

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681113	SCV000808570	uncertain significance	not provided	2018-02-26	criteria provided, single submitter	clinical testing	The C1063R variant in the NF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The C1063R variant is not observed in large population cohorts (Lek et al., 2016). The C1063R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant is located within the GTPase activating protein domain (Xu et al., 1990; Luo et al., 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret C1063R as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861891	SCV002182137	uncertain significance	Neurofibromatosis, type 1	2023-06-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 561736). This variant has not been reported in the literature in individuals affected with NF1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1063 of the NF1 protein (p.Cys1063Arg). 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 not expected to disrupt 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	RCV001861891	SCV002560274	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003163085	SCV003854932	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-02-17	criteria provided, single submitter	clinical testing	The p.C1063R variant (also known as c.3187T>C), located in coding exon 24 of the NF1 gene, results from a T to C substitution at nucleotide position 3187. The cysteine at codon 1063 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.