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NM_000545.8(HNF1A):c.526+1G>A AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 2, 2023
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003446599.1

Allele description [Variation Report for NM_000545.8(HNF1A):c.526+1G>A]

NM_000545.8(HNF1A):c.526+1G>A

Gene:
HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000545.8(HNF1A):c.526+1G>A
HGVS:
  • NC_000012.12:g.120989033G>A
  • NG_011731.2:g.15288G>A
  • NM_000545.8:c.526+1G>AMANE SELECT
  • NM_001306179.2:c.526+1G>A
  • NM_001406915.1:c.526+1G>A
  • LRG_522t1:c.526+1G>A
  • LRG_522:g.15288G>A
  • NC_000012.11:g.121426836G>A
  • NM_000545.5:c.526+1G>A
  • NM_000545.6:c.526+1G>A
Links:
dbSNP: rs1364708195
NCBI 1000 Genomes Browser:
rs1364708195
Molecular consequence:
  • NM_000545.8:c.526+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001306179.2:c.526+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406915.1:c.526+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004174141ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF1A V2.1.0)		Pathogenic
(Dec 2, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004174141.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.526+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1. This variant was identified in 12 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 21242637, internal lab contributors), including an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate, internal lab contributor). This variant segregated with diabetes, with six informative meioses in five families with MODY (PP1_Strong, internal lab collaborators). In summary, c.526+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024