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NM_000545.8(HNF1A):c.864del (p.Pro291fs) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 30, 2021
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:
RCV001810451.3

Allele description [Variation Report for NM_000545.8(HNF1A):c.864del (p.Pro291fs)]

NM_000545.8(HNF1A):c.864del (p.Pro291fs)

Gene:
HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000545.8(HNF1A):c.864del (p.Pro291fs)
Other names:
NM_000545.6(HNF1A):c.864del; p.Pro291fs
HGVS:
  • NC_000012.12:g.120994314del
  • NG_011731.2:g.20569del
  • NM_000545.8:c.864delMANE SELECT
  • NM_001306179.2:c.864del
  • NP_000536.6:p.Pro291fs
  • NP_001293108.2:p.Pro291fs
  • LRG_522:g.20569del
  • NC_000012.11:g.121432115del
  • NC_000012.11:g.121432117del
  • NC_000012.12:g.120994314delG
  • NM_000545.5:c.864delG
  • NM_000545.6:c.864delG
Protein change:
P291fs
Links:
dbSNP: rs762703502
NCBI 1000 Genomes Browser:
rs762703502
Molecular consequence:
  • NM_000545.8:c.864del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001306179.2:c.864del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002059980ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)		Likely pathogenic
(Dec 30, 2021) 		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, SCV002059980.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate

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

Last Updated: Oct 13, 2024