ClinVar Genomic variation as it relates to human health

The p.M1035V variant (also known as c.3103A>G), located in coding exon 23 of the NF1 gene, results from an A to G substitution at nucleotide position 3103. The methionine at codon 1035 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000alleles tested) in our clinical cohort.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.

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1035 of the NF1 protein (p.Met1035Val). This variant is present in population databases (rs771694969, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 9042399, 31573083). ClinVar contains an entry for this variant (Variation ID: 220267). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the p.Met1035 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807336, 9042399, 24789688; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Reported in individuals with suspected or clinically diagnosed neurofibromatosis type 1 (Rodenhiser et al., 1997; Castellanos et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31573083, 9042399, 25486365, 2121369)

The c.3103A>G (p.M1035V) alteration is located in exon 23 (coding exon 23) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 3103, causing the methionine (M) at amino acid position 1035 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.