ClinVar Genomic variation as it relates to human health
NM_001370259.2(MEN1):c.1350+1G>A
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.1350+1G>A
Variation ID: 16707 Accession: VCV000016707.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.1 11: 64805033 (GRCh38) [ NCBI UCSC ] 11: 64572505 (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 May 1, 2024 Aug 14, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- IVS9, G-A, +1
- Canonical SPDI
- NC_000011.10:64805032: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
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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
Help
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 |
2579 | 2600 |
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
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
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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 (1) |
no assertion criteria provided
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Aug 1, 2004 | RCV000018187.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2023 | RCV002381254.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 14, 2023 | RCV003517126.2 |
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
(Mar 29, 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: SCV002690031.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1350+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MEN1 gene. This alteration has … (more)
The c.1350+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MEN1 gene. This alteration has been reported in a Chilean family with familial isolated hyperparathyroidism. RNA analyses on patient leukocytes demonstrated that c.1350+1G>A results in intron retention (Carrasco et al. J Clin Endoc Metab 2004 Aug; 89(8): 4124-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Aug 14, 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: SCV004295812.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Ser555Asn) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MEN1 protein in which other variant(s) (p.Ser555Asn) have been determined to be pathogenic (PMID: 9683585, 15254225, 21819486). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in retention of intron 9 which introduces a premature stop codon and introduces a new termination codon (PMID: 29416715). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 16707). Disruption of this splice site has been observed in individual(s) with hyperparathyroidism and/or multiple endocrine neoplasia type 1 (PMID: 15292357, 29416715). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the MEN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. (less)
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Pathogenic
(Aug 01, 2004)
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no assertion criteria provided
Method: literature only
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HYPERPARATHYROIDISM, FAMILIAL ISOLATED PRIMARY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038466.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2017 |
Comment on evidence:
In a Chilean family with familial isolated primary hyperparathyroidism (FIHP; 145000), Carrasco et al. (2004) identified a heterozygous G-to-A transition at nucleotide 7361 of the … (more)
In a Chilean family with familial isolated primary hyperparathyroidism (FIHP; 145000), Carrasco et al. (2004) identified a heterozygous G-to-A transition at nucleotide 7361 of the tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9+1G-A). All 11 family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and wildtype sequences. RT-PCR analyses showed an abnormal mRNA of greater size (829 bp) in the mutated MEN1 gene than the normal transcript (629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. The authors concluded that this mutation produces an aberrant splicing of mRNA that could lead to a truncated protein without activity, explaining the clinical picture of this patient and his family. (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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Long-term follow-up and novel splice donor mutation in MEN1 in a Chinese family. | Li M | Oncotarget | 2017 | PMID: 29416715 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism. | Carrasco CA | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15292357 |
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 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs863223311 ...
HelpRecord last updated Sep 29, 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.