Submissions for variant NM_001042492.3(NF1):c.3544G>T (p.Val1182Phe)

dbSNP: rs1555615027

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544954	SCV000628528	pathogenic	Neurofibromatosis, type 1	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1182 of the NF1 protein (p.Val1182Phe). 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 (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 457654). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001571922	SCV001796480	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Identified in individuals with suspected or clinically diagnosed neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Yao et al., 2019; Hazan et al., 2021); Not observed in large population cohorts (gnomAD); 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: 31717729, 33443663, 2121369, 25486365, 22807134, 26582918, 23656349)
Genome-Nilou Lab	RCV000544954	SCV002559969	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159753	SCV003893708	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-23	criteria provided, single submitter	clinical testing	The p.V1182F variant (also known as c.3544G>T), located in coding exon 27 of the NF1 gene, results from a G to T substitution at nucleotide position 3544. The valine at codon 1182 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was reported as de novo in an individual with clinical features of neurofibromatosis 1 (NF1) (Yao R et al. Genes (Basel), 2019 10;10:). It was also detected in the heterozygous state in an individual who met National Institutes of Health criteria for NF1 (Hazan F et al. Neurol Sci, 2021 May;42:2045-2057). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GenomeConnect - Invitae Patient Insights Network	RCV001535486	SCV001749424	not provided	Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 04-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.