ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.130del (p.Leu44fs)
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.130del (p.Leu44fs)
Variation ID: 36798 Accession: VCV000036798.6
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 120978894 (GRCh38) [ NCBI UCSC ] 12: 121416697 (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 Nov 29, 2022 Apr 2, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000545.8:c.130del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Leu44fs frameshift NM_001306179.2:c.130del NP_001293108.2:p.Leu44fs frameshift NC_000012.12:g.120978898del NC_000012.11:g.121416701del NG_011731.2:g.5153del LRG_522:g.5153del LRG_522t1:c.130del - Protein change
- L44fs
- Other names
- NM_000545.8(HNF1A):c.130del
- p.Leu44fs
- Canonical SPDI
- NC_000012.12:120978893:CCCCC:CCCC
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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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HNF1A | - | - |
GRCh38 GRCh37 |
865 | 954 |
Conditions - Germline
Condition
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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
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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) |
criteria provided, single submitter
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Aug 18, 2011 | RCV000030478.3 | |
Pathogenic (1) |
reviewed by expert panel
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Apr 2, 2022 | RCV002222002.3 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2019 | RCV002326697.1 |
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
(Apr 02, 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: SCV002499539.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids … (more)
The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 15305805). This variant segregated with diabetes, with at least five informative meioses in two families with MODY (PP1_Strong; PMIDs: 15305805 and 12453976). This variant was Identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 15305805 and 12453976). In summary, c.130delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4. (less)
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Pathogenic
(Feb 23, 2019)
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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: SCV002693601.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.130delC pathogenic mutation, located in coding exon 1 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 130, causing … (more)
The c.130delC pathogenic mutation, located in coding exon 1 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 130, causing a translational frameshift with a predicted alternate stop codon (p.L44Wfs*111). This mutation was identified in multiple individuals from two maturity-onset diabetes of the young families (Klupa T et al. Diabetes Care, 2002 Dec;25:2292-301; McKinney JL et al. Clin Invest Med, 2004 Jun;27:135-41). In addition to the clinical data presented 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)
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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MODY3
(autosomal dominant)
Affected status: yes, unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053148.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 4
Observation 2:
Number of individuals with the variant: 3
Observation 3:
Tissue: Blood
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Likely pathogenic
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002601655.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. … (more)
Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs193922578 with MODY3. (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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Meta-analysis of HNF1A-MODY3 variants among human population. | Behl R | Journal of diabetes and metabolic disorders | 2022 | PMID: 35673428 |
HNF1A Mutations and Beta Cell Dysfunction in Diabetes. | Miyachi Y | International journal of molecular sciences | 2022 | PMID: 35328643 |
Altered cortisol metabolism in individuals with HNF1A-MODY. | Juszczak A | Clinical endocrinology | 2020 | PMID: 32395877 |
Novel insights into genetics and clinics of the HNF1A-MODY. | Valkovicova T | Endocrine regulations | 2019 | PMID: 31517624 |
Spectrum of HNF1A and GCK mutations in Canadian families with maturity-onset diabetes of the young (MODY). | McKinney JL | Clinical and investigative medicine. Medecine clinique et experimentale | 2004 | PMID: 15305805 |
Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1alpha mutations: evidence for parent-of-origin effect. | Klupa T | Diabetes care | 2002 | PMID: 12453976 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4fa9ddcb-687e-47a2-80ec-5c1d1073e80b | - | - | - | - |
Text-mined citations for rs193922578 ...
HelpRecord last updated Nov 29, 2022
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.