ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1321T>A (p.Trp441Arg) (rs104894259)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255755 SCV000321887 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing The W436R variant has previously been reported in at least one individual undergoing genetic testing of the MEN1 gene at an outside clinical laboratory (Klein et al., 2005). Functional studies have shown that the W436R mutant protein is not stable and is rapidly degraded by the ubiquitin-proteasome pathway (Canaff et al., 2012). This variant is not observed in large population cohorts (Lek et al., 2016). The XW436R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. An alternate nucleotide change resulting in the same amino acid change (c.1306T>C) has been reported in association with multiple endocrine neoplasia type 1, supporting the functional importance of this region of the protein (Agarwal et al., 1997; Chandrasekharappa et al., 1997). Based on the currently available information, we consider W436R to be pathogenic.
Invitae RCV000018166 SCV000831725 pathogenic Multiple endocrine neoplasia, type 1 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 436 of the MEN1 protein (p.Trp436Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with multiple endocrine neoplasia type 1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 16686). The p.Trp436Arg substitution has been shown to reduce the expression of menin protein in vitro (PMID: 21819486). In addition, it interferes with the interaction between menin and AKT1 kinase thereby disrupts ATK1-mediated anti-apoptosis effect in endocrine cells (PMID: 21127195) A different variant (c.1306T>C) giving rise to the same protein effect observed here (p.Trp436Arg) has been reported in individuals affected with multiple endocrine neoplasia type 1 (PMID: 9103196, 15714081), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018166 SCV000038445 pathogenic Multiple endocrine neoplasia, type 1 1997-04-18 no assertion criteria provided literature only

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