ClinVar Miner

Submissions for variant NM_020975.6(RET):c.588G>C (p.Leu196Phe)

dbSNP: rs2132684107
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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 RCV002010146 SCV002278651 uncertain significance Multiple endocrine neoplasia, type 2 2021-09-15 criteria provided, single submitter clinical testing 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 phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 196 of the RET protein (p.Leu196Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. 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.
Sema4, Sema4 RCV002256884 SCV002527917 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-18 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV002010146 SCV005430295 uncertain significance Multiple endocrine neoplasia, type 2 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 196 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. 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.
Ambry Genetics RCV002256884 SCV005491058 uncertain significance Hereditary cancer-predisposing syndrome 2024-09-12 criteria provided, single submitter clinical testing The p.L196F variant (also known as c.588G>C), located in coding exon 3 of the RET gene, results from a G to C substitution at nucleotide position 588. The leucine at codon 196 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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