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

gnomAD frequency: 0.00009  dbSNP: rs772222326

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005236511	SCV005887585	likely benign	not specified	2025-01-23	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.142G>A (p.Glu48Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 1612500 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). c.142G>A has been reported in the literature in individuals affected with diabetes, however definitive causal association with the disorder and this variant were unclear (e.g., Gal_2021, Johansen_2005, Juszczak_2019, Moller_1998, Thanabalasingham_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effects resulting in 61% of normal trancriptional activity and 75% of normal nuclear localization compared to wild type (Najmi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 34440499, 15928245, 30455330, 9867222, 27899486, 23274891). ClinVar contains an entry for this variant (Variation ID: 806957). Based on the evidence outlined above, the variant was classified as likely benign.