Submissions for variant NM_001042492.3(NF1):c.3277G>A (p.Val1093Met)

dbSNP: rs1555614858

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537710	SCV000628507	pathogenic	Neurofibromatosis, type 1	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1093 of the NF1 protein (p.Val1093Met). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10862084, 18546366, 23913538). ClinVar contains an entry for this variant (Variation ID: 457638). 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%. Studies have shown that this missense change results in a new splice site within exon 25 and deletes 40 nucleotides from the exon, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10862084, 23913538; internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004701610	SCV005202043	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (PMID: 10862084, 18546366, 23913538); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23913538, 10862084, 18546366, 31370276, 25486365, 2121369)
Rajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences	RCV000537710	SCV002499633	likely pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research	The NF1 gene encodes Neurofibromin, a cytoplasmic protein that is predominantly expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes. Mutations in NF1 result in Neurofibromatosis type 1 with an autosomal dominant inheritance (OMIM: 162200).