ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2410G>C (p.Val804Leu) (rs79658334)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479688 SCV000565490 pathogenic not provided 2017-01-10 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.2410G>C at the cDNA level, p.Val804Leu (V804L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). RET Val804Leu has been published numerous times in association with familial medullary thyroid cancer (FMTC) and has also been reported in families with multiple endocrine neoplasia type 2 (MEN2A) (Nilsson 1999, Frohnauer and Decker 2000, Lombardo 2002, Patocs 2006, Verrienti 2015). Of note, variants at codon 804 have been associated with a lower penetrance (Mukherjee and Zakalik 2011). Functional assays have demonstrated that RET Val804Leu induces autophosphorylation of tyrosine residues and transformation activity in fibroblasts (Pasini 1997, Iwashita 1999). RET Val804Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. RET Val804Leu occurs at a position that is conserved across species and is located in within the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this pathogenic variant may have on protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Research and Development, ARUP Laboratories RCV000021853 SCV000042519 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Single family report, two have the mutation genotype: 2 MTC (54 yr and not given). Additional references: PMID 9384613 and 11114642. Has been found with another RET change, see c.[1942G>A];[2410G>C].
Database of Curated Mutations (DoCM) RCV000425568 SCV000510542 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437130 SCV000510543 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419916 SCV000510544 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426266 SCV000510545 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436948 SCV000510546 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only

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