ClinVar Miner

Submissions for variant NM_002529.4(NTRK1):c.2281C>T (p.Arg761Trp)

gnomAD frequency: 0.00001  dbSNP: rs759637817
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674105 SCV000799381 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2018-04-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674105 SCV000821402 pathogenic Hereditary insensitivity to pain with anhidrosis 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 755 of the NTRK1 protein (p.Arg755Trp). 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 missense change has been observed in individuals with congenital insensitivity to pain with anhidrosis/ hereditary sensory and autonomic neuropathy (PMID: 11668614, 16373086, 19651702, 28192073). This variant is also known as p.Arg761Trp. ClinVar contains an entry for this variant (Variation ID: 557905). 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 NTRK1 protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000674105 SCV002020172 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2019-01-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674105 SCV002600302 pathogenic Hereditary insensitivity to pain with anhidrosis 2022-10-05 criteria provided, single submitter clinical testing Variant summary: NTRK1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 227242 control chromosomes. c.2263C>T has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (example, Indo_2001, Veerpoorten_2006, Rotthier_2009, Lv_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV002442399 SCV002733870 uncertain significance Inborn genetic diseases 2021-04-02 criteria provided, single submitter clinical testing The p.R755W variant (also known as c.2263C>T), located in coding exon 16 of the NTRK1 gene, results from a C to T substitution at nucleotide position 2263. The arginine at codon 755 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected as homozygous or compound heterozygous with other variants in NTRK1 in multiple individuals with congenital insensitivity to pain with anhidrosis (CIPA) (Indo Y et al. Hum Mutat, 2001 Oct;18:308-18; Rotthier A et al. Brain, 2009 Oct;132:2699-711; Lv F et al. Clin Chim Acta, 2017 May;468:39-45). This amino acid position is not well 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.