ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.958G>T (p.Asp320Tyr) (rs747851909)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494086 SCV000582467 pathogenic not provided 2015-08-27 criteria provided, single submitter clinical testing The D315Y missense variant in the MEN1 gene has been reported previously in association with multiple endocrine neoplasia type 1 (White et al., 2010; Ellard et al., 2005). It 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 common benign variant in these populations. D315Y 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 conserved in mammals and in-silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (A309P, T311P, R314P, H317Y/R, P320L/R) have been reported in the Human Gene Mutation Database in association with multiple endocrine neoplasia type 1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the D315Y variant is interpreted as pathogenic.
Invitae RCV001202722 SCV001373847 uncertain significance Multiple endocrine neoplasia, type 1 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 315 of the MEN1 protein (p.Asp315Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs747851909, ExAC 0.001%). This variant has been observed in several individuals and a family affected with clinical features of MEN1-related conditions (PMID: 15670192, 20231234, Invitae). ClinVar contains an entry for this variant (Variation ID: 429809). 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: "Benign"; Align-GVGD: "Class C45"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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