ClinVar Miner

Submissions for variant NM_001007792.1(NTRK1):c.2134C>T (p.Arg712Trp) (rs778520978)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520846 SCV000619463 uncertain significance not provided 2017-07-25 criteria provided, single submitter clinical testing 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.
Invitae RCV000552631 SCV000626961 uncertain significance Hereditary insensitivity to pain with anhidrosis 2019-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 742 of the NTRK1 protein (p.Arg742Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs778520978, ExAC 0.01%). This variant has not been reported in the literature in individuals with an NTRK1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on NTRK1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV000552631 SCV001463414 uncertain significance Hereditary insensitivity to pain with anhidrosis 2020-01-13 no assertion criteria provided clinical testing

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