ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1312G>A (p.Val438Ile) (rs774474422)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540480 SCV000658403 uncertain significance Multiple endocrine neoplasia, type 2 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 438 of the RET protein (p.Val438Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs774474422, ExAC 0.009%) but has not been reported in the literature in individuals with a RET-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000663209 SCV000786393 uncertain significance Multiple endocrine neoplasia, type 2a 2018-04-24 criteria provided, single submitter clinical testing

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