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NM_000545.8(HNF1A):c.526+2dup AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 15, 2022
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:
RCV002250371.3

Allele description [Variation Report for NM_000545.8(HNF1A):c.526+2dup]

NM_000545.8(HNF1A):c.526+2dup

Gene:
HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000545.8(HNF1A):c.526+2dup
Other names:
NM_000545.6(HNF1A):c.526+2dup
HGVS:
  • NC_000012.12:g.120989034dup
  • NG_011731.2:g.15289dup
  • NM_000545.8:c.526+2dupMANE SELECT
  • NM_001306179.2:c.526+2dup
  • LRG_522t1:c.526+2dup
  • LRG_522:g.15289dup
  • NC_000012.11:g.121426836_121426837insT
  • NC_000012.11:g.121426837dup
  • NM_000545.5:c.526+2dup
Links:
dbSNP: rs1555211448
NCBI 1000 Genomes Browser:
rs1555211448
Molecular consequence:
  • NM_000545.8:c.526+2dup - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001306179.2:c.526+2dup - 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
SCV002520630ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)		Uncertain significance
(Apr 15, 2022) 		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, SCV002520630.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.526+2dup 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result greater than 50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). This variant was identified in three 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 (internal lab contributors). In summary, c.526+2dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PP4_Moderate, PP3.

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

Last Updated: Sep 29, 2024