ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.2T>C (p.Met1Thr)
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_000545.8(HNF1A):c.2T>C (p.Met1Thr)
Variation ID: 1342949 Accession: VCV001342949.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120978770 (GRCh38) [ NCBI UCSC ] 12: 121416573 (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 Mar 12, 2022 Apr 20, 2024 Aug 26, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Met1Thr missense initiator codon variant NM_001306179.2:c.2T>C NP_001293108.2:p.Met1Thr missense initiator codon variant NC_000012.12:g.120978770T>C NC_000012.11:g.121416573T>C NG_011731.2:g.5025T>C LRG_522:g.5025T>C LRG_522t1:c.2T>C - Protein change
- M1T
- Other names
- NM_001306179.2:c.2T>C
- Canonical SPDI
- NC_000012.12:120978769:T:C
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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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- Links
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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HNF1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
872 | 958 |
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) |
reviewed by expert panel
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Aug 26, 2022 | RCV001843399.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2022 | RCV002440900.2 |
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
(Aug 26, 2022)
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reviewed by expert panel
Method: curation
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Monogenic diabetes
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Monogenic Diabetes Variant Curation Expert Panel
Accession: SCV002102532.3
First in ClinVar: Mar 12, 2022 Last updated: Sep 03, 2023 |
Comment:
The c.2T>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start … (more)
The c.2T>C variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1?) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 18003757, PMID: 23348805, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 was not applied (internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2, approved 8/4/2022): PVS1, PS4_Moderate, PM2_Supporting. (less)
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Likely pathogenic
(Apr 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002748828.2
First in ClinVar: Nov 29, 2022 Last updated: Sep 03, 2023 |
Comment:
The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the HNF1A gene, results from a T to C substitution at nucleotide … (more)
The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the HNF1A gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This variant has been detected in three families with clinical diagnoses of MODY; however, specific phenotype information was not provided (Bellanné-Chantelot C, Diabetes 2008 Feb; 57(2):503-8; Colclough K, Hum. Mutat. 2013 May; 34(5):669-85.). Of note, the nucleotide changes observed in these studies, which all result in the same p.M1? alteration, include c.1A>C, c.1A>T, and c.2T>C. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6449 samples (12898 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, this alteration is interpreted as likely pathogenic (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). (less)
Number of individuals with the variant: 1
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Likely Pathogenic
(Dec 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848879.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Met1? (c.2T>C) variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young (MODY) (Colclough 2013 PMID: 23348805). It was … (more)
The p.Met1? (c.2T>C) variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young (MODY) (Colclough 2013 PMID: 23348805). It was absent from large population studies. This variant was classified as Likely Pathogenic on Mar 4, 2022 by the ClinGen-approved Monogenic Diabetes expert panel (Variation ID 1342949). It affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an downstream translation initiation codon) are possible. Additional variants involving the initiation codon (c.1A>C, c.1A>T) have been identified in individuals with MODY (Colclough 2013 PMID: 23348805, Bellanné-Chantelot 2008 PMID: 18003757), supporting that this change may not be tolerated. Loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant MODY. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2_P. (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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Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. | Colclough K | Human mutation | 2013 | PMID: 23348805 |
The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. | Bellanné-Chantelot C | Diabetes | 2008 | PMID: 18003757 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/97e49de0-8fd2-41f5-a2be-3977a5292f20 | - | - | - | - |
Text-mined citations for rs2135819325 ...
HelpRecord last updated Apr 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.