Submissions for variant NM_001042492.3(NF1):c.3104T>C (p.Met1035Thr)

dbSNP: rs137854553

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV000497241	SCV000588757	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000523086	SCV000617579	likely pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	Observed in an individual with a diagnosis or clinical suspicion of neurofibromatosis type 1 (Xu et al., 2014); 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; This variant is associated with the following publications: (PMID: Martorana2022[CaseReport], 25486365, 2121369, 24789688, 26582918, 24077912, 31370276, 34080803)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497241	SCV000951363	pathogenic	Neurofibromatosis, type 1	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1035 of the NF1 protein (p.Met1035Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a clinical diagnosis or suspicion of neurofibromatosis type 1 (PMID: 24789688; Invitae). ClinVar contains an entry for this variant (Variation ID: 431618). 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. This variant disrupts the p.Met1035 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (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.
Genome-Nilou Lab	RCV000497241	SCV002560262	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323858	SCV002605931	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-07	criteria provided, single submitter	clinical testing	The p.M1035T variant (also known as c.3104T>C), located in coding exon 23 of the NF1 gene, results from a T to C substitution at nucleotide position 3104. The variant has been reported in an individual with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). The methionine at codon 1035 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.