ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2370G>C (p.Leu790Phe) (rs75030001)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182583 SCV000234935 pathogenic not provided 2017-07-21 criteria provided, single submitter clinical testing The L790F missense variant in the RET gene has previously been reported in association with RET-related disorders (for examples, see Machens et al., 2001; Romei et al., 2010). Another missense variant at this position (c.2380G>T) resulting in the same amino acid change was also reported in association with RET-related disorders (Fitze et al., 2002; Machens et al., 2008; Bihan et al., 2012). The L790F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a benign variant in these populations. Therefore, given the available data, we consider L790F to be pathogenic, and its presence is consistent with the diagnosis of a RET-related disorder in this individual.
Counsyl RCV000014960 SCV000784781 likely pathogenic Multiple endocrine neoplasia, type 2a 2017-12-26 criteria provided, single submitter clinical testing
Invitae RCV000021849 SCV000934365 pathogenic Multiple endocrine neoplasia, type 2 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 790 of the RET protein (p.Leu790Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs75030001, ExAC 0.002%). This variant has been observed in several individuals and families with medullary thyroid carcinoma (PMID: 12490841, 18062802) and to segregate with disease in at least one family (PMID: 9506724). ClinVar contains an entry for this variant (Variation ID: 13935). Experimental studies have shown that the cell growth activity of this missense variant is similar to the wild-type. However, this variant may impact a function that was not assessed by this study (PMID: 21810974). A different variant (c.2370G>T) giving rise to the same protein effect observed here (p.Leu790Phe), as well as the p.Leu790Phe change without a reported nucleotide change, have been reported in many individuals affected with medullary thyroid carcinoma (PMID: 9506724, 23756355, 21688339, 12409662, 22965292, 14561794, 20833330, 20516206, 25767701), indicating that this residue may be critical for protein function. Notably, the p.Leu790Phe variant is associated with a less aggressive form of multiple endocrine neoplasia type 2, with fewer cases of pheochromocytoma compared to other pathogenic RET variants (PMID: 12490841, 12409662, 16868135, 21688339, 23756355). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014960 SCV000035216 pathogenic Multiple endocrine neoplasia, type 2a 1998-03-01 no assertion criteria provided literature only
OMIM RCV000014961 SCV000035217 pathogenic Familial medullary thyroid carcinoma 1998-03-01 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021849 SCV000042515 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Median age of MTC onset, 57 yr. Additional references: PMID 16314641, 18062802 and 12490841.

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