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

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002829720	SCV003218724	pathogenic	Neurofibromatosis, type 1	2023-12-07	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 (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2013853). 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.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; 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.
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)