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NM_000545.8(HNF1A):c.526+1G>T 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:
RCV003445171.1

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

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

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>T
Other names:
NM_001306179.2:c.526+1G>T
HGVS:
  • NC_000012.12:g.120989033G>T
  • NG_011731.2:g.15288G>T
  • NM_000545.8:c.526+1G>TMANE SELECT
  • NM_001306179.2:c.526+1G>T
  • NM_001406915.1:c.526+1G>T
  • LRG_522t1:c.526+1G>T
  • LRG_522:g.15288G>T
  • NC_000012.11:g.121426836G>T
  • NM_000545.5:c.526+1G>T
Molecular consequence:
  • NM_000545.8:c.526+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001306179.2:c.526+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406915.1:c.526+1G>T - 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
    SCV004174143ClinGen 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, SCV004174143.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedcurationnot provided

    Description

    The c.526+1G>T 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 (PM2_Supporting). The HNF1A(NM_000545.8):c.526+1G>A and c.526+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>T has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33bp 65%) (PS1_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information. This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP. In summary, c.526+1G>T 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, PS1_Supporting, PM2_Supporting.

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

    Last Updated: May 1, 2024