ClinVar Miner

Submissions for variant NM_020975.6(RET):c.664G>A (p.Glu222Lys)

dbSNP: rs1837729713
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001308859 SCV001498333 uncertain significance Multiple endocrine neoplasia, type 2 2022-10-17 criteria provided, single submitter clinical testing 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1011103). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 27986441). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 222 of the RET protein (p.Glu222Lys).
GeneDx RCV003229888 SCV003927592 uncertain significance not provided 2022-11-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)
Ambry Genetics RCV004034183 SCV005028289 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-10 criteria provided, single submitter clinical testing The p.E222K variant (also known as c.664G>A), located in coding exon 4 of the RET gene, results from a G to A substitution at nucleotide position 664. The glutamic acid at codon 222 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV001308859 SCV005430303 uncertain significance Multiple endocrine neoplasia, type 2 2024-04-16 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 222 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with pheochromocytoma (PMID: 27986441). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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