Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001030785 | SCV002237780 | pathogenic | Hereditary insensitivity to pain with anhidrosis | 2022-10-07 | criteria provided, single submitter | clinical testing | 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 expected to disrupt NTRK1 protein function. ClinVar contains an entry for this variant (Variation ID: 810634). This missense change has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 18162686, 29770739). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs763122825, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 718 of the NTRK1 protein (p.Gly718Ser). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001030785 | SCV004122112 | pathogenic | Hereditary insensitivity to pain with anhidrosis | 2023-10-25 | criteria provided, single submitter | clinical testing | Variant summary: NTRK1 c.2152G>A (p.Gly718Ser), also known as c.2170G>A (p.Gly724Ser) in NM_002529, results in a non-conservative amino acid change to a highly conserved residue (HGMD) 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 8e-06 in 251156 control chromosomes (gnomAD). c.2152G>A has been reported in the literature in multiple individuals affected with Hereditary Insensitivity To Pain With Anhidrosis (Shalimar_2007, Geng_2018, Echaniz-Laguna_2021, Khaled_2023), and at least one individual was reported as compound heterozygous with a pathogenic variant. 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: 18162686, 29770739, 34405299, 37248554). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Section for Clinical Neurogenetics, |
RCV001030785 | SCV001156095 | likely pathogenic | Hereditary insensitivity to pain with anhidrosis | 2019-08-01 | no assertion criteria provided | research |