ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1429G>T (p.Glu477Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001370259.2(MEN1):c.1429G>T (p.Glu477Ter)
Variation ID: 216133 Accession: VCV000216133.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64572210 (GRCh37) [ NCBI UCSC ] 11: 64804738 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 7, 2017 Feb 20, 2024 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370259.2:c.1429G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Glu477Ter nonsense NM_000244.4:c.1444G>T NP_000235.3:p.Glu482Ter nonsense NM_001370251.2:c.1555G>T NP_001357180.2:p.Glu519Ter nonsense NM_001370260.2:c.1429G>T NP_001357189.2:p.Glu477Ter nonsense NM_001370261.2:c.1429G>T NP_001357190.2:p.Glu477Ter nonsense NM_001370262.2:c.1324G>T NP_001357191.2:p.Glu442Ter nonsense NM_001370263.2:c.1324G>T NP_001357192.2:p.Glu442Ter nonsense NM_130799.3:c.1429G>T NP_570711.2:p.Glu477Ter nonsense NM_130800.3:c.1444G>T NP_570712.2:p.Glu482Ter nonsense NM_130801.3:c.1444G>T NP_570713.2:p.Glu482Ter nonsense NM_130802.3:c.1444G>T NP_570714.2:p.Glu482Ter nonsense NM_130803.3:c.1444G>T NP_570715.2:p.Glu482Ter nonsense NM_130804.3:c.1444G>T NP_570716.2:p.Glu482Ter nonsense NC_000011.10:g.64804738C>A NC_000011.9:g.64572210C>A NG_008929.1:g.11557G>T NG_033040.1:g.3504G>T LRG_509:g.11557G>T LRG_509t2:c.1429G>T LRG_509p2:p.Glu477Ter - Protein change
- E477*, E482*, E519*, E442*
- Other names
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- Canonical SPDI
- NC_000011.10:64804737:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MEN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2417 | 2434 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000198067.23 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 5, 2023 | RCV000254822.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 6, 2022 | RCV000490934.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547634.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: MEN1 c.1429G>T (p.Glu477X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MEN1 c.1429G>T (p.Glu477X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 225462 control chromosomes. c.1429G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (eg. Cote_1998, Dackiw_1999, Klein_2005, Kouvaraki_2002, etc). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000579669.5
First in ClinVar: Jun 25, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.E477* pathogenic mutation (also known as c.1429G>T), located in coding exon 9 of the MEN1 gene, results from a G to T substitution at … (more)
The p.E477* pathogenic mutation (also known as c.1429G>T), located in coding exon 9 of the MEN1 gene, results from a G to T substitution at nucleotide position 1429. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration occurs at the 3' terminus of theMEN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 134 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been detected in seven affected members of one family (Kouvaraki MA et al. Arch Surg. 2002 Jun;137(6):641-7). In addition to the clinical data presented in the literature, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774387.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This nonsense variant causes the premature termination of MEN1 protein synthesis. In addition, it has been reported in symptomatic individuals with multiple endocrine neoplasia 1 … (more)
This nonsense variant causes the premature termination of MEN1 protein synthesis. In addition, it has been reported in symptomatic individuals with multiple endocrine neoplasia 1 in the published literature (PMIDs: 12049533 (2002) and 15714081 (2005)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321888.11
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more)
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Identified in patients with multiple endocrine neoplasia type 1 referred for genetic testing at this laboratory and in published literature (Cote 1998, Dackiw 1999, Kouvaraki 2002, Klein 2005); This variant is associated with the following publications: (PMID: 15714081, 17879353, 12049533, 10660339, 10598193, 15281352) (less)
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Pathogenic
(Feb 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019132.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024336.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000253966.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu477*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Glu477*) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 134 amino acid(s) of the MEN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with multiple endocrine neoplasia 1 (MEN1) (PMID: 12049533, 15714081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216133). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation (PMID: 15331604, 16449969). While functional studies have not been performed to directly test the effect of this variant on MEN1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158284.4
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The MEN1 c.1429G>T; p.Glu477Ter variant (rs863224526) is reported in the medical literature in individuals and families with a clinical diagnosis of multiple endocrine neoplasia type … (more)
The MEN1 c.1429G>T; p.Glu477Ter variant (rs863224526) is reported in the medical literature in individuals and families with a clinical diagnosis of multiple endocrine neoplasia type 1 (Dackiw 1999, Klein 2005, Kouvaraki 2002). The variant is described as pathogenic in the ClinVar database (Variation ID: 216133) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MEN1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Considering available information, this variant is classified as pathogenic. References: Dackiw AP et al. Screening for MEN1 mutations in patients with atypical endocrine neoplasia. Surgery. 1999 Dec;126(6):1097-103. PMID: 10598193. Klein RD et al. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb;7(2):131-8. PMID: 15714081. Kouvaraki MA et al. Genotype-phenotype analysis in multiple endocrine neoplasia type 1. Arch Surg. 2002 Jun;137(6):641-7. PMID: 12049533. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. | Klein RD | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 15714081 |
Genotype-phenotype analysis in multiple endocrine neoplasia type 1. | Kouvaraki MA | Archives of surgery (Chicago, Ill. : 1960) | 2002 | PMID: 12049533 |
Screening for MEN1 mutations in patients with atypical endocrine neoplasia. | Dackiw AP | Surgery | 1999 | PMID: 10598193 |
Five novel mutations in the familial multiple endocrine neoplasia type 1 (MEN1) gene. Mutations in brief no. 188. Online. | Cote GJ | Human mutation | 1998 | PMID: 10660339 |
Text-mined citations for rs863224526 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.