ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs772222326
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV001174362 SCV002499497 likely benign Monogenic diabetes 2022-04-08 reviewed by expert panel curation 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.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001174362 SCV001337500 uncertain significance Monogenic diabetes 2019-01-25 criteria provided, single submitter research 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)
GeneDx RCV000994997 SCV001801304 likely benign not provided 2021-03-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32910913, 15928245, 27899486, 9867222, 24097065, 23274891, 30455330)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000994997 SCV002009080 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Invitae RCV000994997 SCV002221833 uncertain significance not provided 2022-03-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 48 of the HNF1A protein (p.Glu48Lys). This variant is present in population databases (rs772222326, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of HNF1A-related conditions (PMID: 9867222, 15928245, 23274891). ClinVar contains an entry for this variant (Variation ID: 806957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 27899486). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002464352 SCV002605555 uncertain significance Maturity onset diabetes mellitus in young criteria provided, single submitter research Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs772222326 with MODY3.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.