Submissions for variant NM_020975.6(RET):c.1299C>G (p.Phe433Leu)

dbSNP: rs1554818526

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654579	SCV000776473	uncertain significance	Multiple endocrine neoplasia, type 2	2024-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 433 of the RET protein (p.Phe433Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 543743). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV001010584	SCV001170807	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The p.F433L variant (also known as c.1299C>G), located in coding exon 7 of the RET gene, results from a C to G substitution at nucleotide position 1299. The phenylalanine at codon 433 is replaced by leucine, an amino acid with highly 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	RCV000654579	SCV004817843	uncertain significance	Multiple endocrine neoplasia, type 2	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 433 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.
GeneDx	RCV004777808	SCV005389938	uncertain significance	not provided	2024-04-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates 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)
PreventionGenetics, part of Exact Sciences	RCV004544908	SCV004783301	uncertain significance	RET-related disorder	2024-03-29	no assertion criteria provided	clinical testing	The RET c.1299C>G variant is predicted to result in the amino acid substitution p.Phe433Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.