Submissions for variant NM_002529.4(NTRK1):c.2231del (p.Arg744fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002425896	SCV002730830	likely pathogenic	Inborn genetic diseases	2021-05-21	criteria provided, single submitter	clinical testing	The c.2213delG variant, located in coding exon 16 of the NTRK1 gene, results from a deletion of one nucleotide at nucleotide position 2213, causing a translational frameshift with a predicted alternate stop codon (p.R738Lfs*76). This alteration occurs at the 3' terminus of theNTRK1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 22 amino acids. This frameshift impacts the last 7% (54amino acids) of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098720	SCV003488815	pathogenic	Hereditary insensitivity to pain with anhidrosis	2022-09-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NTRK1 protein in which other variant(s) (p.Arg765Cys) have been determined to be pathogenic (PMID: 27265460, 27676246, 32219930). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the NTRK1 gene (p.Arg738Leufs*76). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the NTRK1 protein and extend the protein by 22 additional amino acid residues.
Genome-Nilou Lab	RCV003098720	SCV004048778	likely pathogenic	Hereditary insensitivity to pain with anhidrosis	2023-04-11	criteria provided, single submitter	clinical testing