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NM_000545.8(HNF1A):c.427del (p.His143fs) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 29, 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:
RCV001794551.3

Allele description [Variation Report for NM_000545.8(HNF1A):c.427del (p.His143fs)]

NM_000545.8(HNF1A):c.427del (p.His143fs)

Gene:
HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q24.31
Genomic location:
Preferred name:
NM_000545.8(HNF1A):c.427del (p.His143fs)
Other names:
NM_001306179.2:c.427del
HGVS:
  • NC_000012.12:g.120988933del
  • NG_011731.2:g.15188del
  • NM_000545.8:c.427delMANE SELECT
  • NM_001306179.2:c.427del
  • NP_000536.6:p.His143fs
  • NP_001293108.2:p.His143fs
  • LRG_522:g.15188del
  • NC_000012.11:g.121426736del
Protein change:
H143fs
Links:
dbSNP: rs2135832675
NCBI 1000 Genomes Browser:
rs2135832675
Molecular consequence:
  • NM_000545.8:c.427del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001306179.2:c.427del - 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
SCV002032350ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)		Likely pathogenic
(Oct 29, 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, SCV002032350.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.427del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 143 (NM_000545.8), adding 12 novel amino acids before encountering a stop codon (p.(His143ThrfsTer12)). This variant, located in biologically-relevant exon 2 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). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 18003757, internal lab contributor). Additionally, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting.

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

Last Updated: Dec 24, 2023