ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1423C>T (p.Arg475Trp) (rs746512075)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693492 SCV000821363 uncertain significance Multiple endocrine neoplasia, type 2 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 475 of the RET protein (p.Arg475Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs746512075, ExAC 0.01%). This variant has been reported in an individual affected with Hirschsprung disease (PMID: 11955539). ClinVar contains an entry for this variant (Variation ID: 572175). Experimental studies using a cell-based secretion assay have shown that this missense change might minimally affect the maturation efficiency and secretion of the RET protein (PMID: 20473317). 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.
Mendelics RCV000709109 SCV000838379 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011519 SCV001171850 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient evidence

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