Submissions for variant NM_002529.4(NTRK1):c.641G>A (p.Arg214Gln)

gnomAD frequency: 0.00023  dbSNP: rs200132482

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000285911	SCV000349045	uncertain significance	Hereditary insensitivity to pain with anhidrosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000489659	SCV000577439	uncertain significance	not provided	2017-03-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NTRK1 gene. The R214Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R214Q variant is observed in 3/2,518 (0.1%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R214Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000285911	SCV000752363	likely benign	Hereditary insensitivity to pain with anhidrosis	2024-01-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489659	SCV002544329	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	NTRK1: PM2, BP4
Ambry Genetics	RCV002365333	SCV002661236	uncertain significance	Inborn genetic diseases	2020-08-10	criteria provided, single submitter	clinical testing	The p.R214Q variant (also known as c.641G>A), located in coding exon 6 of the NTRK1 gene, results from a G to A substitution at nucleotide position 641. The arginine at codon 214 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000285911	SCV002086533	uncertain significance	Hereditary insensitivity to pain with anhidrosis	2020-01-17	no assertion criteria provided	clinical testing