Submissions for variant NM_001007792.1(NTRK1):c.163C>A (p.Arg55Ser)

gnomAD frequency: 0.00004  dbSNP: rs543320028

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000986439	SCV001135440	likely pathogenic	Hereditary insensitivity to pain with anhidrosis	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000986439	SCV001520942	uncertain significance	Hereditary insensitivity to pain with anhidrosis	2020-03-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001585661	SCV001821304	uncertain significance	not specified	2021-08-19	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000986439	SCV002252424	uncertain significance	Hereditary insensitivity to pain with anhidrosis	2022-06-23	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002424729	SCV002742454	uncertain significance	Inborn genetic diseases	2020-12-31	criteria provided, single submitter	clinical testing	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.
Inherited Neuropathy Consortium	RCV000789505	SCV000928861	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Natera, Inc.	RCV000986439	SCV002086502	uncertain significance	Hereditary insensitivity to pain with anhidrosis	2020-02-13	no assertion criteria provided	clinical testing