Submissions for variant NM_001042492.3(NF1):c.4235G>T (p.Arg1412Ile)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002829720	SCV003218724	pathogenic	Neurofibromatosis, type 1	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 1391 of the NF1 protein (p.Arg1391Ile). 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: 2013853). 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%. This variant disrupts the p.Arg1391 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7581973, 9003501, 16513807, 22807134, 27322474; internal data). 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.
Baylor Genetics	RCV003465845	SCV004190762	likely pathogenic	Juvenile myelomonocytic leukemia	2023-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV004765575	SCV005376751	likely pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365, 22807134)
Ambry Genetics	RCV004990885	SCV005454147	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-09-25	criteria provided, single submitter	clinical testing	The p.R1391I variant (also known as c.4172G>T), located in coding exon 31 of the NF1 gene, results from a G to T substitution at nucleotide position 4172. The arginine at codon 1391 is replaced by isoleucine, an amino acid with similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with neurofibromatosis type 1 (Ambry internal data). Another variant at the same codon, p.R1391T (c.4172G>C), has been identified in multiple individuals who met clinical criteria for neurofibromatosis type 1 (van Minkelen R et al. Clin Genet, 2014 Apr;85:318-27; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Evans DG et al. EBioMedicine, 2016 May;7:212-20). Based on internal structural analysis, R1391I disrupts an invariant arginine which participates in intramolecular interactions critical to proper function (Ambry internal data; Scheffzek K et al. Science, 1997 Jul;277:333-8; Sermon BA et al. J Biol Chem, 1998 Apr;273:9480-5; Naschberger A et al. Nature, 2021 Nov;599:315-319). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.