Submissions for variant NM_002529.4(NTRK1):c.1474G>A (p.Glu492Lys)

gnomAD frequency: 0.00040  dbSNP: rs144901788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486476	SCV000566265	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22302274, 27058611, 32707200, 34426522, 33235206, 35101157)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631332	SCV000752362	likely benign	Hereditary insensitivity to pain with anhidrosis	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317235	SCV004020758	uncertain significance	not specified	2023-06-02	criteria provided, single submitter	clinical testing	Variant summary: NTRK1 c.1456G>A (p.Glu486Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 250934 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NTRK1 causing Hereditary Insensitivity To Pain With Anhidrosis (0.00045 vs 0.0011), allowing no conclusion about variant significance. c.1456G>A has been reported in the literature in individuals affected with sensory and autonomic neuropathy, presumed ocular histoplasmosis syndrome, as well as in a large pedigree, in which bipolar disorder co-segregated with autosomal dominant tubulointerstitial kidney disease (Davidson_2012, Li_2020, Nakajima_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Insensitivity To Pain With Anhidrosis. At least one functional study showed E492K NSCs (neural stem cells) had reduced neurite outgrowth and a conditional knock-in mouse line showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor (Nakajima_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22302274, 32707200, 33235206). Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000486476	SCV004701533	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	NTRK1: PM2, PP3
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