ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1424G>A (p.Arg475Gln) (rs138624658)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148779 SCV000190517 uncertain significance Hirschsprung disease 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Invitae RCV000470554 SCV000543838 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 475 of the RET protein (p.Arg475Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138624658, ExAC 0.01%). This variant has been observed in an individual affected with Hirschsprung disease (PMID: 20473317). ClinVar contains an entry for this variant (Variation ID: 135188). 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 glutamine 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.
ITMI RCV000121995 SCV000086206 not provided not specified 2013-09-19 no assertion provided reference population

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