Submissions for variant NM_001042492.3(NF1):c.5651T>G (p.Phe1884Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470271	SCV002767003	likely pathogenic	Neurofibromatosis, type 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis, type 1 (MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SEC14 domain and pleckstrin homology domain (PMID: 30290804). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Phe1884Leu)) has been reported once as a VUS (LOVD). It has also been reported as likely pathogenic and pathogenic, and observed in several individuals with neurofibromatosis (NF) (ClinVar, PMID: 27838393, PMID: 30308447). Another comparable variant (p.(Phe1884Val)) has been reported as a VUS (ClinVar, LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed in a single individual with NF (PMID: 30290804) and reported as pathogenic (LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470271	SCV004296780	uncertain significance	Neurofibromatosis, type 1	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1863 of the NF1 protein (p.Phe1863Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 30290804). ClinVar contains an entry for this variant (Variation ID: 1805987). 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.Phe1863 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22190595, 27838393; Invitae). 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.