chr1-156881532-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_002529.4(NTRK1):c.2281C>T(p.Arg761Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000873 in 1,602,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R761Q) has been classified as Likely benign.
Frequency
Consequence
NM_002529.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.2281C>T | p.Arg761Trp | missense_variant | 17/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.2263C>T | p.Arg755Trp | missense_variant | 16/16 | ||
NTRK1 | NM_001007792.1 | c.2173C>T | p.Arg725Trp | missense_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.2281C>T | p.Arg761Trp | missense_variant | 17/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000896 AC: 13AN: 1450644Hom.: 0 Cov.: 31 AF XY: 0.00000971 AC XY: 7AN XY: 720724
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74384
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 17, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 25, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2022 | Variant summary: NTRK1 c.2263C>T (p.Arg755Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 227242 control chromosomes. c.2263C>T has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (example, Indo_2001, Veerpoorten_2006, Rotthier_2009, Lv_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 755 of the NTRK1 protein (p.Arg755Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with congenital insensitivity to pain with anhidrosis/ hereditary sensory and autonomic neuropathy (PMID: 11668614, 16373086, 19651702, 28192073). This variant is also known as p.Arg761Trp. ClinVar contains an entry for this variant (Variation ID: 557905). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NTRK1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2021 | The p.R755W variant (also known as c.2263C>T), located in coding exon 16 of the NTRK1 gene, results from a C to T substitution at nucleotide position 2263. The arginine at codon 755 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected as homozygous or compound heterozygous with other variants in NTRK1 in multiple individuals with congenital insensitivity to pain with anhidrosis (CIPA) (Indo Y et al. Hum Mutat, 2001 Oct;18:308-18; Rotthier A et al. Brain, 2009 Oct;132:2699-711; Lv F et al. Clin Chim Acta, 2017 May;468:39-45). This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at