ClinVar Miner

Submissions for variant NM_002529.4(NTRK1):c.2119G>A (p.Glu707Lys)

gnomAD frequency: 0.00001  dbSNP: rs747855434
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000631320 SCV000752349 uncertain significance Hereditary insensitivity to pain with anhidrosis 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 701 of the NTRK1 protein (p.Glu701Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs747855434, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. 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. 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.
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV001270189 SCV001364320 likely pathogenic Premature ovarian failure 2020-03-02 criteria provided, single submitter research
Genome-Nilou Lab RCV000631320 SCV001737236 uncertain significance Hereditary insensitivity to pain with anhidrosis 2021-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004525991 SCV005040045 uncertain significance not specified 2024-03-07 criteria provided, single submitter clinical testing Variant summary: NTRK1 c.2101G>A (p.Glu701Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2101G>A has been reported in the literature in one individual affected with primary ovarian insufficiency (Bestetti_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Insensitivity To Pain With Anhidrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34480478). ClinVar contains an entry for this variant (Variation ID: 526718). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000631320 SCV001456802 uncertain significance Hereditary insensitivity to pain with anhidrosis 2020-09-16 no assertion criteria provided clinical testing

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