Submissions for variant NM_001042492.3(NF1):c.2998C>T (p.Arg1000Cys)

gnomAD frequency: 0.00001  dbSNP: rs367684252

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552854	SCV000628480	pathogenic	Neurofibromatosis, type 1	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1000 of the NF1 protein (p.Arg1000Cys). This variant is present in population databases (rs367684252, gnomAD 0.006%). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 25074460, 27838393, 34080803). ClinVar contains an entry for this variant (Variation ID: 457616). 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.Arg1000 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002316497	SCV000670395	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-21	criteria provided, single submitter	clinical testing	The p.R1000C variant (also known as c.2998C>T), located in coding exon 23 of the NF1 gene, results from a C to T substitution at nucleotide position 2998. The arginine at codon 1000 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in several individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Pasmant E et al. Eur. J. Hum. Genet., 2015 May;23:596-601; Calì F et al. Eur J Med Genet, 2017 Feb;60:93-99; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9(12):e1631). This alteration has not been reported in 7051 unselected female breast cancer patients and with a frequency of 0.00009% in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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 this alteration remains unclear.
GeneDx	RCV001591197	SCV001826773	uncertain significance	not provided	2022-12-14	criteria provided, single submitter	clinical testing	Observed in individuals with neurofibromatosis type 1 and in healthy controls (Pasmant et al., 2015, Cali et al., 2017, Rasouly et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21520333, 29636988, 29489754, 30476936, 31645765, 25074460, 27838393, 33563663, 26076063, 30287823, 34080803, 25486365, 2121369)
Genome-Nilou Lab	RCV000552854	SCV002560248	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737610	SCV005361897	uncertain significance	NF1-related disorder	2024-05-14	no assertion criteria provided	clinical testing	The NF1 c.2998C>T variant is predicted to result in the amino acid substitution p.Arg1000Cys. This variant has been reported in two individuals with neurofibromatosis type 1 (Pasmant et al. 2015. PubMed ID: 25074460; Calì et al. 2016. PubMed ID: 27838393) and in an individual with Burkitt's lymphoma (Gröbner et al. 2018. PubMed ID: 29489754). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. It has conflicting classifications in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/457616/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.