ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1888T>C (p.Cys630Arg) (rs377767404)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654593 SCV000776487 pathogenic Multiple endocrine neoplasia, type 2 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 630 of the RET protein (p.Cys630Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals with familial medullary thyroid cancer (FMTC), and reported to segregate with FMTC in several families (PMID: 15523405, 16053382, 14561794, 25440022). ClinVar contains an entry for this variant (Variation ID: 24908). Experimental studies have shown that this missense change causes constitutive activation of the RET protein, and therefore results in gain-of-function in vitro (PMID: 9879991). A different missense substitution at this codon (p.Cys630Tyr) has been determined to be pathogenic (PMID: 21054478, 17527003, 9223675). This suggests that the cysteine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000654593 SCV000042472 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Youngest with MTC: 15 yr. One case of HPT (PMID 15523405). In vitro studies: RET activation (PMID 9879991). Additional references: PMID 16053382.
Database of Curated Mutations (DoCM) RCV000429498 SCV000510462 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436253 SCV000510463 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418588 SCV000510464 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428845 SCV000510465 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440788 SCV000510466 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only

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