ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1825T>C (p.Cys609Arg) (rs77558292)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414355 SCV000490767 pathogenic not provided 2015-06-16 criteria provided, single submitter clinical testing The C609R pathogenic variant has been report previously in association with multiple endocrine neoplasia type 2A (Kambouris et al., 1996; Barbieri et al., 2013). In vitro function studies demonstrated that C609R confers a gain-of-function to the protein resulting in enhanced tyrosine autophosphorylation and the ability to phosphorylate downstream target effectors (Chappuis-Flament et al., 1998). The C609R substitution was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C609R variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C609S, C609G, C609R, C609F, C609Y, C609W) have been reported in the Human Gene Mutation Database in association with RET-related disorders (Stenson et al., 2014). Therefore, we interpret C609R as a pathogenic variant.
Ambry Genetics RCV001013275 SCV001173842 pathogenic Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing 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;Rarity in general population databases (dbsnp, esp, 1000 genomes);Well-characterized mutation at same position
OMIM RCV000014971 SCV000035227 pathogenic Familial medullary thyroid carcinoma 2000-09-04 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021776 SCV000042442 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 27 yr. Youngest with Pheo: 22 yr (PMID 15771139). Patients may also have HSCR (PMID 10982477, 17895320 and 17188172). In vitro studies: RET activation (PMID 9879991). Additional references: PMID 20979234, 14561794 and 16707008.
Human Genomics Unit,Institute for molecular medicine Finland (FIMM) RCV000736274 SCV000864571 likely pathogenic Hirschsprung disease 2013-01-01 no assertion criteria provided research

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