ClinVar Miner

Submissions for variant NM_001007792.1(NTRK1):c.1366G>A (p.Glu456Lys) (rs144901788)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486476 SCV000566265 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NTRK1 gene. The E486K variant hasbeen reported previously using alternate nomenclature, E492K, in the homozygous state in anindividual with congenital sensory neuropathy with associated anhidrosis, seizures, hearing loss, and developmental delay (Davidson et al., 2012). The E486K variant has also been reported in the compound heterozygous state with a second variant in the NTRK1 gene in an individual who underwent whole exome sequencing for an atrioventricular septal defect (Priest et al., 2016). The E486K variant is observed in 57/66622 (0.09%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The E486K variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000631332 SCV000752362 uncertain significance Hereditary insensitivity to pain with anhidrosis 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 486 of the NTRK1 protein (p.Glu486Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs144901788, ExAC 0.09%). This variant has been reported in the homozygous state in an individual affected with congenital sensory neuropathy with associated anhidrosis, seizures, deafness and developmental delay (PMID: 22302274), and in combination with another NTRK1 variant in a cohort of individuals affected with atrioventricular septal heart defects (PMID: 27058611). This variant is also known as E492K in the literature. ClinVar contains an entry for this variant (Variation ID: 418887). 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, 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.
Illumina Clinical Services Laboratory,Illumina RCV000631332 SCV001258310 uncertain significance Hereditary insensitivity to pain with anhidrosis 2017-10-25 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000486476 SCV001713862 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789503 SCV000928859 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Natera, Inc. RCV000631332 SCV001454778 uncertain significance Hereditary insensitivity to pain with anhidrosis 2020-09-16 no assertion criteria provided clinical testing

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