ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: NTRK1 c.253C>A (p.Arg85Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251346 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.253C>A has been reported in the literature to co-occur in-cis with a pathogenic variant (c.429-1G>C) in a homozygous individual affected with Hereditary Insensitivity To Pain With Anhidrosis (Mardy_1999). It has also been reported to segregate with disease in two compound heterozygous siblings that had inherited each of their variants from their carrier parents (Hartono_2020). These reports do not allow any unequivocal conclusions about significance of the variant. Experimental evidence evaluating an impact on protein function through utilization of a combination of biochemical and biological assays, demonstrated the variant to have similar activity to wild-type (Mardy_2001, Miranda_2002). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 85 of the NTRK1 protein (p.Arg85Ser). This variant is present in population databases (rs543320028, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 10330344, 32707409). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584593). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. Experimental studies have shown that this missense change does not substantially affect NTRK1 function (PMID: 11719521). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.R85S variant (also known as c.253C>A), located in coding exon 2 of the NTRK1 gene, results from a C to A substitution at nucleotide position 253. The arginine at codon 85 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in the homozygous state in an individual with congenital insensitivity to pain with anhidrosis (CIPA) who also had another homozygous variant in NTRK1 (c.429-1G>C) (Mardy S et al. Am J Hum Genet, 1999 Jun;64:1570-9). In addition, the p.R85S variant was found to segregate with CIPA in two affected siblings with CIPA, who were both compound heterozygotes for NTRK1 p.R85S (c.253C>A) and p.R692C (c.2074C>T) (Hartono F et al. Int J Surg Case Rep, 2020 Jul;73:213-217). Protein functional studies suggest that this alteration does not impair normal processing or autophosphorylation of NTRK1 (Mardy S et al. Hum Mol Genet, 2001 Feb;10:179-88; Miranda C et al. J Biol Chem, 2002 Feb;277:6455-62). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.