ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1597G>A (p.Gly533Ser) (rs75873440)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573056 SCV000674831 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409959 SCV000489747 uncertain significance Multiple endocrine neoplasia, type 2b 2015-12-10 criteria provided, single submitter clinical testing
Counsyl RCV000411509 SCV000489748 uncertain significance Multiple endocrine neoplasia, type 2a 2015-12-10 criteria provided, single submitter clinical testing
Invitae RCV000465806 SCV000543800 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 533 of the RET protein (p.Gly533Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs75873440, ExAC 0.06%). This variant has been reported in the literature in individuals affected with Hirschsprung disease (PMID: 23084198, 26395553) and paraganglioma or pheochromocytoma (PMID: 22517557). ClinVar contains an entry for this variant (Variation ID: 24887). An experimental study has shown that this missense change does not affect phosphorylation of the RET and ERK proteins compared to the wild-type RET protein (PMID: 26395553). A different missense substitution at this codon (p.Gly533Cys) has been determined to be pathogenic (PMID: 14602786, 16649977, 22676047, 23461807, 18805915). This suggests that the glycine residue is critical for RET protein function and that other missense substitutions at this position may also be damaging. 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.
Research and Development, ARUP Laboratories RCV000021768 SCV000042434 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only Variant found in a Thai sporadic HSCR patient. Not screened for MEN2. Patient also had Down syndrome (2-10% have HSCR).

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