ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.65T>G (p.Leu22Arg) (rs104894256)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182402 SCV000234745 likely pathogenic not provided 2016-02-23 criteria provided, single submitter clinical testing The L22R variant in the MEN1 gene has previously been reported in association with multiple endocrine neoplasia type 1 (MEN1) (for examples, see Chandrasekharappa et al., 1997; Simonds et al., 2012). In vitro functional studies indicate L22R is expressed at markedly reduced levels compared to wild-type protein, and led to unstable protein which affects binding with other proteins (Agarwal et al., 1999; Canaff et al., 2012). Another functional study has demonstrated that L22R mutant protein is unable to repress Gas1 expression in Hedgehog signaling compared to wildtype menin (Gurung et al., 2013). The L22R variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L22R 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. This substitution occurs at a position that is conserved across species. A missense variant in nearby residue E26K has been reported in association with MEN1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
OMIM RCV000018157 SCV000038436 pathogenic Multiple endocrine neoplasia, type 1 1997-04-18 no assertion criteria provided literature only

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