ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2449C>T (p.Arg817Cys) (rs142318626)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411874 SCV000489843 uncertain significance Multiple endocrine neoplasia, type 2b 2016-05-20 criteria provided, single submitter clinical testing
Counsyl RCV000409506 SCV000489844 uncertain significance Multiple endocrine neoplasia, type 2a 2016-05-20 criteria provided, single submitter clinical testing
GeneDx RCV000414497 SCV000490770 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing This variant is denoted RET c.2449C>T at the cDNA level, p.Arg817Cys (R817C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RET Arg817Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RET Arg817Cys occurs at a position that is conserved across species and is located in the Tyrosine kinase domain (Garcia-Barcelo 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RET Arg817Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123311 SCV000166618 uncertain significance Multiple endocrine neoplasia, type 2 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 817 of the RET protein (p.Arg817Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs142318626, ExAC 0.01%). This variant has not been reported in the literature in individuals with RET-related disease. ClinVar contains an entry for this variant (Variation ID: 136111). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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