ClinVar Genomic variation as it relates to human health

A variant of uncertain significance has been identified in the NTRK1 gene. The R742W variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R742W variantis not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium etal., 2015; Exome Variant Server). The R742W variant is a non-conservative amino acid substitution, which is likelyto impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a conserved position predicted to be within the protein kinase domain. In silico analysispredicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently availableinformation, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 742 of the NTRK1 protein (p.Arg742Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 450841). 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 not expected to disrupt NTRK1 protein function. 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.

The c.2224C>T (p.R742W) alteration is located in exon 16 (coding exon 16) of the NTRK1 gene. This alteration results from a C to T substitution at nucleotide position 2224, causing the arginine (R) at amino acid position 742 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

NTRK1: PM2, PP3

Variant interpreted as Uncertain significance and reported on 07-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.