ClinVar Miner

Submissions for variant NM_001007792.1(NTRK1):c.1949G>A (p.Arg650His) (rs754452975)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000174855 SCV000226236 uncertain significance not provided 2015-04-03 criteria provided, single submitter clinical testing
Invitae RCV000528062 SCV000626956 uncertain significance Hereditary insensitivity to pain with anhidrosis 2019-05-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 680 of the NTRK1 protein (p.Arg680His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs754452975, ExAC 0.006%). This variant has been reported in an individual affected with congenital insensitivity to pain with anhidrosis (PMID: 23799134). This variant is also referred to as p.Arg686His in the literature. ClinVar contains an entry for this variant (Variation ID: 194476). 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, this variant has uncertain impact on NTRK1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000528062 SCV000915361 uncertain significance Hereditary insensitivity to pain with anhidrosis 2017-04-28 criteria provided, single submitter clinical testing The NTRK1 c.2039G>A (p.Arg680His) missense variant (also referred to as c.2057G>A, p.Arg686His), has been reported in one study in which it is found in a compound heterozygous state with a second missense variant in one individual with congenital insensitivity to pain with anhidrosis (Gao et al. 2013). The variant was also found in a heterozygous state in one of the unaffected parents. The p.Arg680His variant was absent from 100 controls and is reported at a frequency of 0.00006 in the South Asian population, however this is based on one allele so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg680His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for congenital insensitivity to pain with anhidrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Natera, Inc. RCV000528062 SCV001456801 uncertain significance Hereditary insensitivity to pain with anhidrosis 2020-09-16 no assertion criteria provided clinical testing

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