Submissions for variant NM_002529.4(NTRK1):c.2074C>T (p.Arg692Cys)

gnomAD frequency: 0.00002  dbSNP: rs761967383

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001958041	SCV002209017	pathogenic	Hereditary insensitivity to pain with anhidrosis	2023-01-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg686 amino acid residue in NTRK1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23799134; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1439142). This variant is also known as c.2074C>T, p.(Arg692Cys). This missense change has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 27265460, 29770739, 30774415). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs761967383, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 686 of the NTRK1 protein (p.Arg686Cys).
Neuberg Centre For Genomic Medicine, NCGM	RCV001958041	SCV004047633	pathogenic	Hereditary insensitivity to pain with anhidrosis		criteria provided, single submitter	clinical testing	The c.2074C>T (p.Arg692Cys) missense variant in NTRK1 gene has been reported in heterozygous state in individuals affected with with hereditary sensory and autonomic neuropathy (Wang et al., 2016; Geng et al., 2018). This missense variant is expected to disrupt NTRK1 protein function. It has been submitted to ClinVar as a Pathogenic variant. This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. The amino acid Arg at position 692 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg692Cys in NTRK1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699572	SCV005205300	uncertain significance	not specified	2024-06-04	criteria provided, single submitter	clinical testing	Variant summary: NTRK1 c.2056C>T (p.Arg686Cys), also referred to as c.2074C>T(p.Arg692Cys), 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 1.6e-05 in 250700 control chromosomes. c.2056C>T has been reported in the literature in at least one heterozyous and two compound heterozygous individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (e.g. Wang_2016, Geng_2018, Li_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29770739, 30774415). ClinVar contains an entry for this variant (Variation ID: 1439142). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001958041	SCV005678529	likely pathogenic	Hereditary insensitivity to pain with anhidrosis	2024-06-10	criteria provided, single submitter	clinical testing