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NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys) AND Monogenic diabetes

Germline classification:
Likely benign (2 submissions)
Last evaluated:
Apr 8, 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:
RCV001174362.12

Allele description [Variation Report for NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys)]

NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys)

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.142G>A (p.Glu48Lys)
Other names:
NM_001306179.1:c.142G>A
HGVS:
  • NC_000012.12:g.120978910G>A
  • NG_011731.2:g.5165G>A
  • NM_000545.8:c.142G>AMANE SELECT
  • NM_001306179.2:c.142G>A
  • NP_000536.6:p.Glu48Lys
  • NP_001293108.2:p.Glu48Lys
  • LRG_522t1:c.142G>A
  • LRG_522:g.5165G>A
  • NC_000012.11:g.121416713G>A
  • NC_000012.11:g.121416713G>A
  • NM_000545.5:c.142G>A
  • NM_000545.6:c.142G>A
Protein change:
E48K
Links:
dbSNP: rs772222326
NCBI 1000 Genomes Browser:
rs772222326
Molecular consequence:
  • NM_000545.8:c.142G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.142G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001337500Personalized Diabetes Medicine Program, University of Maryland School of Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 25, 2019)
unknownresearch

PubMed (3)
[See all records that cite these PMIDs]

SCV002499497ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)
Likely benign
(Apr 8, 2022)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknown1not providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1.

Johansen A, Ek J, Mortensen HB, Pedersen O, Hansen T.

J Clin Endocrinol Metab. 2005 Aug;90(8):4607-14. Epub 2005 May 31.

PubMed [citation]
PMID:
15928245

Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes.

Møller AM, Dalgaard LT, Pociot F, Nerup J, Hansen T, Pedersen O.

Diabetologia. 1998 Dec;41(12):1528-31.

PubMed [citation]
PMID:
9867222
See all PubMed Citations (3)

Details of each submission

From Personalized Diabetes Medicine Program, University of Maryland School of Medicine, SCV001337500.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (3)

Description

ACMG criteria: BS1 (0.00016 in EurNF gnomAD population); variant found in PMIDs: 15928245 and 9867222, patients in which do not have clear HNF1A MODY phenotype and authors did not look at many genes= VUS (REVEL 0.691 + PP3/6 predictors + BP4/3 predictors= conflicting evidence, not using)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot provided1not providednot providednot provided

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV002499497.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.142G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to lysine at codon 48 (p.(Glu48Lys)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). Functional studies demonstrated the p.Glu48Lys protein has normal nuclear localization, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 27899486). This variant was identified in at least 5 unrelated individuals with diabetes, but members of at least two families had evidence of autoimmunity; also, the variant does not meet the PM2_Supporting cutoff (PMID: 15928245, internal lab contributor). Therefore, PS4 could not be applied. This variant was not identified in any individuals with calculated MODY probability >=50%; therefore, PP4 could not be applied. In summary, c.142G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BS1, BS3_Supporting.

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

Last Updated: Jul 15, 2024