ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.552G>C (p.Glu184Asp) (rs1555165811)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521106 SCV000620425 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing The E179D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E179D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. An alternate nucleotide change leading to the same missense variant (c.537G>T) has been reported in association with multiple endocrine neoplasia type 1, supporting the functional importance of this region of the protein (Poncin et al., 1999). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001228587 SCV001400992 uncertain significance Multiple endocrine neoplasia, type 1 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 179 of the MEN1 protein (p.Glu179Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed to segregate with multiple endocrine neoplasia type 1 (MEN1) in a family, and has been observed in individuals with clinical features of MEN1 (PMID: 11102994, Invitae). ClinVar contains an entry for this variant (Variation ID: 451692). 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"). This variant disrupts the p.179 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 9888389, 11102994, 10849016, 22470073), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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