ClinVar Miner

Submissions for variant NM_002529.3(NTRK1):c.2281C>T (p.Arg761Trp) (rs759637817)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674105 SCV000799381 likely pathogenic Hereditary insensitivity to pain with anhidrosis 2018-04-17 criteria provided, single submitter clinical testing
Invitae RCV000674105 SCV000821402 uncertain significance Hereditary insensitivity to pain with anhidrosis 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 755 of the NTRK1 protein (p.Arg755Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous and/or in combination with another NTRK1 variant in several individuals affected with congenital insensitivity to pain with anhidrosis/ hereditary sensory and autonomic neuropathy (PMID: 11668614, 16373086, 28192073, 19651702). This variant is also known as p.Arg761Trp in the literature. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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