ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1252G>A (p.Asp418Asn)
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.1252G>A (p.Asp418Asn)
Variation ID: 16703 Accession: VCV000016703.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64805132 (GRCh38) [ NCBI UCSC ] 11: 64572604 (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 Apr 4, 2013 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001370259.2:c.1252G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001357188.2:p.Asp418Asn missense NM_000244.4:c.1267G>A NP_000235.3:p.Asp423Asn missense NM_001370251.2:c.1378G>A NP_001357180.2:p.Asp460Asn missense NM_001370260.2:c.1252G>A NP_001357189.2:p.Asp418Asn missense NM_001370261.2:c.1252G>A NP_001357190.2:p.Asp418Asn missense NM_001370262.2:c.1147G>A NP_001357191.2:p.Asp383Asn missense NM_001370263.2:c.1147G>A NP_001357192.2:p.Asp383Asn missense NM_130799.3:c.1252G>A NP_570711.2:p.Asp418Asn missense NM_130800.3:c.1267G>A NP_570712.2:p.Asp423Asn missense NM_130801.3:c.1267G>A NP_570713.2:p.Asp423Asn missense NM_130802.3:c.1267G>A NP_570714.2:p.Asp423Asn missense NM_130803.3:c.1267G>A NP_570715.2:p.Asp423Asn missense NM_130804.3:c.1267G>A NP_570716.2:p.Asp423Asn missense NC_000011.10:g.64805132C>T NC_000011.9:g.64572604C>T NG_008929.1:g.11163G>A NG_033040.1:g.3110G>A LRG_509:g.11163G>A LRG_509t1:c.1267G>A LRG_509p1:p.Asp423Asn LRG_509t2:c.1252G>A LRG_509p2:p.Asp418Asn O00255:p.Asp423Asn - Protein change
- D418N, D423N, D383N, D460N
- Other names
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- Canonical SPDI
- NC_000011.10:64805131:C:T
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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
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
2579 | 2600 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2023 | RCV000018183.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV000490854.11 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV001269702.18 |
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
Help
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
Help
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
Help
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
(Sep 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 1
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712008.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Asp423Asn variant in MEN1 has been reported in least 4 individuals with ME N1 and segregated with disease in at least 8 relatives from … (more)
The p.Asp423Asn variant in MEN1 has been reported in least 4 individuals with ME N1 and segregated with disease in at least 8 relatives from 1 family (Turner 200 2, Vierimaa 2007, Crepin 2003). It was also absent from large population studies . In vitro functional studies provide some evidence that the p.Asp423Asn variant may impact protein function (Shimazu 2011, Yaguchi 2004). In summary, this vari ant meets criteria to be classified as pathogenic for MEN1 in an autosomal domin ant manner based upon segregation studies, absence from controls, and functional evidence studies. (less)
Number of individuals with the variant: 3
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Pathogenic
(Oct 20, 2021)
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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: SCV002048705.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The MEN1 c.1252G>A; p.Asp418Asn variant (rs104894264) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 syndrome (Basset … (more)
The MEN1 c.1252G>A; p.Asp418Asn variant (rs104894264) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 1 syndrome (Basset 1998, Goroshi 2016, Kytola 2001, Verges 2002). Functional analyses show the variant protein is unstable and is rapidly degraded by the ubiquitin-proteasome pathway (Shimazu 2011, Yaguchi 2004). This variant is reported in ClinVar (Variation ID: 16703), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartic acid at codon 418 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.891). Based on available information, this variant is considered to be pathogenic. References: Bassett JH et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 1998 Feb;62(2):232-44. PMID: 9463336. Goroshi M et al. Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India. Fam Cancer. 2016 Oct;15(4):617-24. PMID: 26905068. Kytola S et al. Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. J Med Genet. 2001 Mar;38(3):185-9. PMID: 11303512. Shimazu S et al. Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. Cancer Sci. 2011 Nov;102(11):2097-102. PMID: 21819486. Verges B et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab. 2002 Feb;87(2):457-65. PMID: 11836268. Yaguchi H et al. Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway. Mol Cell Biol. 2004 Aug;24(15):6569-80. PMID: 15254225. (less)
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Pathogenic
(Aug 21, 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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Baylor Genetics
Accession: SCV004194457.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 31, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090894.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
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Pathogenic
(Feb 15, 2017)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449894.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Multiple Endocrine Neoplasia Type 1
(autosomal dominant)
Affected status: yes, unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052862.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 2
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Tissue: Blood
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Pathogenic
(Feb 20, 2023)
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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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Athena Diagnostics
Accession: SCV004229775.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic … (more)
This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21819486, 15254225) (less)
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Pathogenic
(Dec 16, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000291276.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 418 of the MEN1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 418 of the MEN1 protein (p.Asp418Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 1 (MEN1) (PMID: 9463336, 10762295, 11303512, 11836268, 12050235, 12112656, 12652570, 17766710). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16703). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MEN1 function (PMID: 15254225, 21819486). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 11, 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: SCV000579629.6
First in ClinVar: Jun 25, 2017 Last updated: May 01, 2024 |
Comment:
The p.D418N pathogenic mutation (also known as c.1252G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at … (more)
The p.D418N pathogenic mutation (also known as c.1252G>A), located in coding exon 8 of the MEN1 gene, results from a G to A substitution at nucleotide position 1252. The aspartic acid at codon 418 is replaced by asparagine, an amino acid with highly similar properties. This pathogenic mutation was previously reported in two unrelated probands diagnosed with MEN1, with a history of parathyroid tumors and a carcinoid tumor, and was absent in 55 unrelated normal controls (Bassett et al. Am. J. Hum. Genet. 1998;62:232-244). This mutation was also seen to co-segregate with disease in a family with tumors of the parathyroid gland, endocrine pancreas, and anterior pituitary (Giraud et al. Am. J. Hum. Genet.1998 Aug;63(2):455-67), as well as in a family with parathyroid carcinoma, adrenal lesions, and pancreatic neuroendocrine tumors (Cinque L et al. Endocr Connect. 2017 Nov;6(8):886-891). In another study, this mutation is noted to be involved in the JunD-binding domains and is predicted to prevent menin's repressive action on JunD-mediated transcription (Turner et al. J Clin Endocrinol Metab. 2002;87:2688-2693). Furthermore, other functional studies have demonstrated reduced stability and expression of the menin protein compared with wild-type (Shimazu S et al. Cancer Sci. 2011 Nov;102(11):2097-102; Yaguchi Het al. Mol. Cell. Biol. 2004 Aug; 24(15):6569-80). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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: SCV000038462.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2017 |
Comment on evidence:
In affected members of 2 families with MEN1 (131100), Turner et al. (2002) found a heterozygous G-to-A transition at nucleotide 7262 in exon 9 of … (more)
In affected members of 2 families with MEN1 (131100), Turner et al. (2002) found a heterozygous G-to-A transition at nucleotide 7262 in exon 9 of the MEN1 gene, resulting in an asp418-to-asn (D418N) amino acid change. (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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Current concepts in parathyroid carcinoma: a single Centre experience. | Ferraro V | BMC endocrine disorders | 2019 | PMID: 31142320 |
MEN1 gene mutation with parathyroid carcinoma: first report of a familial case. | Cinque L | Endocrine connections | 2017 | PMID: 29097378 |
Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. | Pardi E | PloS one | 2017 | PMID: 29036195 |
Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome. | Mamedova E | Endocrine connections | 2017 | PMID: 28870973 |
Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India. | Goroshi M | Familial cancer | 2016 | PMID: 26905068 |
Genetic and epigenetic analysis in korean patients with multiple endocrine neoplasia type 1. | Chung YJ | Endocrinology and metabolism (Seoul, Korea) | 2014 | PMID: 25309785 |
Metabolic expressivity of human genetic variants: NMR metabotyping of MEN1 pathogenic mutants. | Blaise BJ | Journal of pharmaceutical and biomedical analysis | 2014 | PMID: 24183932 |
Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. | Shimazu S | Cancer science | 2011 | PMID: 21819486 |
Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation. | Vierimaa O | European journal of endocrinology | 2007 | PMID: 17766710 |
Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. | Cetani F | Clinical endocrinology | 2006 | PMID: 16430712 |
Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin-proteasome pathway. | Yaguchi H | Molecular and cellular biology | 2004 | PMID: 15254225 |
Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. | La P | Endocrinology | 2004 | PMID: 15044367 |
Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. | Warner J | Journal of medical genetics | 2004 | PMID: 14985373 |
Efficient mutation detection in MEN1 gene using a combination of single-strand conformation polymorphism (MDGA) and heteroduplex analysis. | Crépin M | Electrophoresis | 2003 | PMID: 12652570 |
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 |
Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. | Vergès B | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 11836268 |
Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland. | Kytölä S | Journal of medical genetics | 2001 | PMID: 11303512 |
Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1. | Hai N | Clinical endocrinology | 2000 | PMID: 10762295 |
Multiple endocrine neoplasia type 1. | Pannett AA | Endocrine-related cancer | 1999 | PMID: 10730900 |
Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. | Teh BT | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9709921 |
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. | Giraud S | American journal of human genetics | 1998 | PMID: 9683585 |
Characterization of mutations in patients with multiple endocrine neoplasia type 1. | Bassett JH | American journal of human genetics | 1998 | PMID: 9463336 |
Somatic mutation of the MEN1 gene in parathyroid tumours. | Heppner C | Nature genetics | 1997 | PMID: 9241276 |
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 rs104894264 ...
HelpRecord last updated Oct 13, 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.