Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001912697 | SCV002170428 | pathogenic | Hereditary insensitivity to pain with anhidrosis | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 765 of the NTRK1 protein (p.Arg765Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 27265460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2311C>T (p.Arg771Cys). ClinVar contains an entry for this variant (Variation ID: 1397970). 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. Experimental studies have shown that this missense change affects NTRK1 function (PMID: 27676246, 32219930). This variant disrupts the p.Arg765 amino acid residue in NTRK1. Other variant(s) that disrupt this residue have been observed in individuals with NTRK1-related conditions (PMID: 30774415), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV004041645 | SCV004993355 | likely pathogenic | Inborn genetic diseases | 2024-02-08 | criteria provided, single submitter | clinical testing | The c.2293C>T (p.R765C) 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 2293, causing the arginine (R) at amino acid position 765 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/242932) total alleles studied. The highest observed frequency was <0.001% (2/20366) of European (Finnish) alleles. This variant has been identified in the homozygous state and in trans with another NTRK1 variant in individuals with features consistent with NTRK1-related congenital insensitivity to pain with anhidrosis (Li, 2019; Geng, 2018; Shaikh, 2017; Wang, 2016). Additionally, another alteration at the same codon, c.2294G>A (p.R765H), has been described in an individual with congenital insensitivity to pain with anhidrosis (Geng, 2018). This amino acid position is highly conserved in available vertebrate species. In an assay testing NTRK1 function, this variant showed a functionally abnormal result (Shaikh, 2017; Zhao, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Fulgent Genetics, |
RCV001912697 | SCV005680682 | likely pathogenic | Hereditary insensitivity to pain with anhidrosis | 2024-01-11 | criteria provided, single submitter | clinical testing |