Submissions for variant NM_002529.4(NTRK1):c.1805G>A (p.Arg602Gln)

dbSNP: rs1647932465

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002538629	SCV003523461	pathogenic	Hereditary insensitivity to pain with anhidrosis	2022-01-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 19651702). 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: 1284518). This variant is also known as c.1697G>A (p.Arg565Gln) and c.1805G>A (p.R602Q). This missense change has been observed in individual(s) with NTRK1-related conditions (PMID: 19651702, 30774415). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 596 of the NTRK1 protein (p.Arg596Gln). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002538629	SCV004037808	pathogenic	Hereditary insensitivity to pain with anhidrosis	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: NTRK1 c.1787G>A (p.Arg596Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the last nucleotide of exon 13, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 5' splicing donor site, and another tool predicts the variant weakens the same 5' donor site. Additionally, two tools predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Rotthier_2009). The variant was absent in 242408 control chromosomes (gnomAD). c.1787G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (e.g., Rotthier_2009, Li_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30774415, 19651702). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV002538629	SCV004048750	pathogenic	Hereditary insensitivity to pain with anhidrosis	2023-04-11	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700866	SCV001918188	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700866	SCV001958073	likely pathogenic	not provided		no assertion criteria provided	clinical testing