ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1546del (p.Arg516fs)
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.1546del (p.Arg516fs)
Variation ID: 200999 Accession: VCV000200999.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64804621 (GRCh38) [ NCBI UCSC ] 11: 64572093 (GRCh37) [ 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 Feb 25, 2017 Feb 14, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370259.2:c.1546del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Arg516fs frameshift NM_000244.4:c.1561del NP_000235.3:p.Arg521fs frameshift NM_001370251.2:c.1672del NP_001357180.2:p.Arg558fs frameshift NM_001370260.2:c.1546del NP_001357189.2:p.Arg516fs frameshift NM_001370261.2:c.1546del NP_001357190.2:p.Arg516fs frameshift NM_001370262.2:c.1441del NP_001357191.2:p.Arg481fs frameshift NM_001370263.2:c.1441del NP_001357192.2:p.Arg481fs frameshift NM_130799.2:c.1546delC frameshift NM_130799.3:c.1546del NP_570711.2:p.Arg516fs frameshift NM_130800.3:c.1561del NP_570712.2:p.Arg521fs frameshift NM_130801.3:c.1561del NP_570713.2:p.Arg521fs frameshift NM_130802.3:c.1561del NP_570714.2:p.Arg521fs frameshift NM_130803.3:c.1561del NP_570715.2:p.Arg521fs frameshift NM_130804.3:c.1561del NP_570716.2:p.Arg521fs frameshift NC_000011.10:g.64804627del NC_000011.9:g.64572099del NG_008929.1:g.11674del NG_033040.1:g.3621del LRG_509:g.11674del LRG_509t2:c.1546del LRG_509p2:p.Arg516fs - Protein change
- R516fs, R481fs, R521fs, R558fs
- Other names
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- Canonical SPDI
- NC_000011.10:64804620:GGGGGGG:GGGGGG
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000182439.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 27, 2023 | RCV000228926.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2023 | RCV001012050.4 |
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
(Mar 21, 2019)
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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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Athena Diagnostics Inc
Accession: SCV001144496.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in … (more)
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. (less)
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Pathogenic
(Oct 31, 2018)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160045.1
First in ClinVar: Feb 09, 2020 Last updated: Feb 09, 2020 |
Comment:
The MEN1 c.1540delC; p.Arg516fs variant (rs794728642), also known as 1650delC or 1656delC, is reported in the literature in multiple individuals affected with multiple endocrine neoplasia … (more)
The MEN1 c.1540delC; p.Arg516fs variant (rs794728642), also known as 1650delC or 1656delC, is reported in the literature in multiple individuals affected with multiple endocrine neoplasia type 1 (Agarwal 1997, Cardinal 2005, Cuny 2013, Ellard 2005, Giraud 1998, Schaaf 2007, Wautot 2002). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 200999), and is found in the Finnish European population with an allele frequency of 0.027% (5/18,304 alleles) in the Genome Aggregation Database. 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 that would include a sequence of 43 amino acid residues not usually present. This variant is predicted to disrupt a nuclear localization signal, and similar disruptions have been shown to abrogate the ability for MEN1 protein to bind DNA and inhibit cell proliferation (La 2004). Based on available information, the p.Arg516fs variant is considered to be pathogenic. References: Agarwal SK et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 1997 Jul;6(7):1169-75. Cardinal JW et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet. 2005 Jan;42(1):69-74. Cuny T et al. Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. Eur J Endocrinol. 2013 Mar 15;168(4):533-41. Ellard S et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005 Feb;62(2):169-75. Giraud S et al. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455-67. La P et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem. 2004 Nov 19;279(47):49045-54. Schaaf L et al. Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. Exp Clin Endocrinol Diabetes. 2007 Sep;115(8):509-17. Wautot V et al. Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002 Jul;20(1):35-47. (less)
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Pathogenic
(Feb 21, 2023)
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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: SCV000234784.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23321498, 9215689, 23933118, 12112656, 11836268, 12050235, 15670192, 10439966, 21916912, 9683585, 12746426, 11966739, 9463336, 17065424, 17853334, 17879353, 11419921, 31482957, 9465067) (less)
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Pathogenic
(Feb 22, 2023)
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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: SCV001172450.4
First in ClinVar: Mar 16, 2020 Last updated: Apr 15, 2023 |
Comment:
The c.1546delC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1546, causing … (more)
The c.1546delC pathogenic mutation, located in coding exon 9 of the MEN1 gene, results from a deletion of one nucleotide at nucleotide position 1546, causing a translational frameshift with a predicted alternate stop codon (p.R516Gfs*43). This mutation has reported in numerous individuals with personal and/or family history consistent with multiple endocrine neoplasia type 1 (Agarwal SK et al, Hum. Mol. Genet. 1997 Jul; 6(7):1169-75;Lemos MC et al, Hum. Mutat. 2008 Jan; 29(1):22-32; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Ventura M et al. Arch Endocrinol Metab, 2019 Sep;63:516-523). Of note, this alterations is also designated as c.1656delC and c.1561del (NM_130802.2) in the literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 27, 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:
germline
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Invitae
Accession: SCV000291287.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg516Glyfs*43) 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.Arg516Glyfs*43) in the MEN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the MEN1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with multiple endocrine neoplasia type 1, or related disorders (PMID: 9215689, 12112656, 12213668, 15670192, 17065424, 17853334, 17879353, 23321498). This variant is also known as 1650delC and 1656delC. ClinVar contains an entry for this variant (Variation ID: 200999). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 14, 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: SCV002766496.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: MEN1 c.1546delC (p.Arg516GlyfsX43) 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.1546delC (p.Arg516GlyfsX43) 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. The variant allele was found at a frequency of 2.5e-05 in 237028 control chromosomes (gnomAD). c.1546delC has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (e.g. Bassett_1998, Cavaco_2002, Cuny_2013). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 30, 2022)
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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: SCV002774391.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This frameshift variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. In the published literature, … (more)
This frameshift variant alters the translational reading frame of the MEN1 mRNA and causes the premature termination of MEN1 protein synthesis. In the published literature, the variant has been reported in affected individuals with multiple endocrine neoplasia type 1 in the published literature (PMIDs: 9215689 (1997), 12112656 (2002), 15670192 (2005), 17853334 (2007), 31482957 (2019), and 32909176 (2021)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 01, 2002)
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no assertion criteria provided
Method: literature only
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038463.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2017 |
Comment on evidence:
In 1 family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a deletion of a C nucleotide at position 7773 in exon 10 … (more)
In 1 family with MEN1 (131100), Turner et al. (2002) found heterozygosity for a deletion of a C nucleotide at position 7773 in exon 10 of the MEN1 gene, resulting in a frameshift and premature termination 42 amino acids after codon 516. (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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Uncommon tumors in multiple endocrine neoplasia (MEN) type 1: Do they have a relationship with the prognosis of these patients? | Febrero B | Journal of endocrinological investigation | 2021 | PMID: 32909176 |
Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1. | Ventura M | Archives of endocrinology and metabolism | 2019 | PMID: 31482957 |
Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. | Concolino P | Cancer genetics | 2016 | PMID: 26767918 |
Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). | Thakker RV | Molecular and cellular endocrinology | 2014 | PMID: 23933118 |
Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis. | Cuny T | European journal of endocrinology | 2013 | PMID: 23321498 |
Multiple endocrine neoplasia type 1. | Thakker RV | Indian journal of endocrinology and metabolism | 2012 | PMID: 23565397 |
Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. | Lemos MC | Human mutation | 2008 | PMID: 17879353 |
Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1. | Schaaf L | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2007 | PMID: 17853334 |
Rapid mutation screening for HRPT2 and MEN1 mutations associated with familial and sporadic primary hyperparathyroidism. | Howell VM | The Journal of molecular diagnostics : JMD | 2006 | PMID: 17065424 |
Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. | La P | Oncogene | 2006 | PMID: 16449969 |
Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. | Ellard S | Clinical endocrinology | 2005 | PMID: 15670192 |
Direct binding of DNA by tumor suppressor menin. | La P | The Journal of biological chemistry | 2004 | PMID: 15331604 |
Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. | Villablanca A | European journal of endocrinology | 2002 | PMID: 12213668 |
Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. | Wautot V | Human mutation | 2002 | PMID: 12112656 |
Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type 1. | Turner JJ | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12050235 |
Mutational analysis of Portuguese families with multiple endocrine neoplasia type 1 reveals large germline deletions. | Cavaco BM | Clinical endocrinology | 2002 | PMID: 11966739 |
Characterization of mutations in patients with multiple endocrine neoplasia type 1. | Bassett JH | American journal of human genetics | 1998 | PMID: 9463336 |
Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. | Agarwal SK | Human molecular genetics | 1997 | PMID: 9215689 |
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Text-mined citations for rs767319284 ...
HelpRecord last updated Feb 20, 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.