ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1444G>T (p.Glu482Ter) (rs863224526)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000490934 SCV000579669 pathogenic Hereditary cancer-predisposing syndrome 2014-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000254822 SCV000321888 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.1429G>T at the cDNA level and p.Glu477Ter (E477X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with features of multiple endocrine neoplasia type 1 (Cote 1998, Dackiw 1999, Kouvaraki 2002, Klein 2005) and is considered pathogenic.
Invitae RCV000198067 SCV000253966 pathogenic Multiple endocrine neoplasia, type 1 2018-10-22 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the MEN1 mRNA at codon 477 (p.Glu477*). It is not anticipated to result in an absent protein by nonsense mediated decay but is expected to create a truncated MEN1 protein missing the C-terminal 134 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in families affected with multiple endocrine neoplasia 1 (MEN1) (PMID: 12049533, 15714081). ClinVar contains an entry for this variant (Variation ID: 216133). This variant, located in the last exon (10), is predicted to result in a truncated MEN1 protein missing an important nuclear localization signal (NLS). Loss of the NLS domain has been shown to disrupt the functional activities of the MEN1 protein (PMID: 16449969). and several other truncating variants in this exon have been reported to be pathogenic (PMID: 15714081). Therefore, the p.Glu477* truncation is expected to be deleterious. For these reasons, this variant has been classified as Pathogenic.

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