ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.518T>C (p.Leu173Pro) (rs386134256)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030205 SCV000052872 pathogenic Multiple endocrine neoplasia, type 1 2018-07-12 criteria provided, single submitter clinical testing Variant summary: MEN1 c.503T>C (p.Leu168Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245690 control chromosomes (in gnomAD). The c.503T>C has been reported in the literature in multiple families with several affected family members with confirmed dx of Multiple Endocrine Neoplasia Type 1 supported by segregation studies (Bartsch 1998, Bartsch 1998 2000, Langer 2001, Schaaf 2007, Waldmann 2007, Waldmann 2009, Ramundo 2014, Giusti 2016, Circelli 2015, Manoharan 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000030205 SCV000944114 pathogenic Multiple endocrine neoplasia, type 1 2019-12-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 168 of the MEN1 protein (p.Leu168Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with multiple endocrine neoplasia type 1 (MEN1) in at least two families (PMID: 9820618, 17853334, 19350320, 25824098), and has been observed in individuals with MEN-1 associated tumors (PMID: 29455199, 26224587). This variant is also known as c.518T>C (p.L173P) in the literature. ClinVar contains an entry for this variant (Variation ID: 36532). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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