ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3185A>G (p.Tyr1062Cys) (rs587778659)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412388 SCV000489763 uncertain significance Multiple endocrine neoplasia, type 2b 2015-12-13 criteria provided, single submitter clinical testing
Counsyl RCV000409698 SCV000489764 uncertain significance Multiple endocrine neoplasia, type 2a 2015-12-13 criteria provided, single submitter clinical testing
ITMI RCV000121983 SCV000086194 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000532140 SCV000658474 uncertain significance Multiple endocrine neoplasia, type 2 2018-10-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1062 of the RET protein (p.Tyr1062Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587778659, ExAC 0.002%). This variant has been reported in the literature in individuals affected with Hirschsprung disease (PMID: 15834508, 22174939, 21995290). ClinVar contains an entry for this variant (Variation ID: 135181). Tyrosine 1062 is located in the TK domain of RET and is also a known docking site for the Shc adaptor protein (PMID: 8663426, 10484767). An experimental study has shown that this missense change significantly decreases the phosphorylation levels of RET and ERK, disturbing RET downstream signaling pathway (PMID: 26395553) In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to affect RET protein function. However, this variant is also present in the general population and segregation studies have not been reported. For these reasons, this change has been classified as a Variant of Uncertain Significance.

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