Submissions for variant NM_020975.6(RET):c.1399G>C (p.Val467Leu)

gnomAD frequency: 0.00002  dbSNP: rs200334340

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497413	SCV000590782	uncertain significance	not provided	2024-12-06	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: 25733075, 14633923)
Ambry Genetics	RCV000575346	SCV000674834	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-05	criteria provided, single submitter	clinical testing	The p.V467L variant (also known as c.1399G>C), located in coding exon 7 of the RET gene, results from a G to C substitution at nucleotide position 1399. The valine at codon 467 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688581	SCV000816200	uncertain significance	Multiple endocrine neoplasia, type 2	2024-11-10	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 467 of the RET protein (p.Val467Leu). This variant is present in population databases (rs200334340, gnomAD 0.004%). 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: 432998). 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 disruptive. 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	RCV000575346	SCV002529927	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291649	SCV002584652	uncertain significance	Multiple endocrine neoplasia type 2A	2022-09-22	criteria provided, single submitter	clinical testing	The RET c.1399G>C (p.Val467Leu) missense change has a maximum subpopulation frequency of 0.0035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 2. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002496914	SCV002806886	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-03-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470621	SCV004208636	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000688581	SCV004820463	uncertain significance	Multiple endocrine neoplasia, type 2	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 467 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 5/251450 chromosomes 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.