Submissions for variant NM_020975.6(RET):c.1183G>C (p.Val395Leu)

gnomAD frequency: 0.00001  dbSNP: rs1452469572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000709107	SCV000838377	uncertain significance	Multiple endocrine neoplasia type 2A	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233523	SCV001406123	uncertain significance	Multiple endocrine neoplasia, type 2	2023-02-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 395 of the RET protein (p.Val395Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 584746). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. 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	RCV002332519	SCV002633567	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	The p.V395L variant (also known as c.1183G>C), located in coding exon 6 of the RET gene, results from a G to C substitution at nucleotide position 1183. The valine at codon 395 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003235370	SCV003933543	uncertain significance	not provided	2022-12-13	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)
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV003403639	SCV004123045	uncertain significance	Pheochromocytoma	2023-07-01	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV001233523	SCV004842607	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-11	criteria provided, single submitter	clinical testing