ClinVar Miner

Submissions for variant NM_002529.3(NTRK1):c.470G>A (p.Arg157His) (rs141021604)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235585 SCV000293127 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing The R157H variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It has been reported three times as a variant of unknown significance in an external database. R157H was not observed with any significant frequency in the 1000 Genomes Project or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R157H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000509462 SCV000752351 uncertain significance Hereditary insensitivity to pain with anhidrosis 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 157 of the NTRK1 protein (p.Arg157His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs141021604, ExAC 0.03%). This variant has not been reported in the literature in individuals with NTRK1-related disease. ClinVar contains an entry for this variant (Variation ID: 245924). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GenomeConnect, ClinGen RCV000509462 SCV000606898 not provided Hereditary insensitivity to pain with anhidrosis no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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