Submissions for variant NM_000545.8(HNF1A):c.50T>A (p.Leu17His)

gnomAD frequency: 0.00001  dbSNP: rs1480672278

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002069315	SCV002495707	uncertain significance	Monogenic diabetes	2022-04-01	reviewed by expert panel	curation	The c.50T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to histidine at codon 17 (p.(Leu17His)) of NM_000545.6. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP threshold of 0.70 (PP3). This variant was observed in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin deficient diabetes (PMID 21683639, internal lab contributor); however, PS4_Moderate cannot be applied because the minimum number of cases is not met. Allele frequency in gnomAD 2.1.1 and 3.1.2 was >0.00002; therefore, PM2_Supporting was not met. The variant segregated with diabetes in one informative meiosis in one family (internal lab contributor); however, this does not meet the threshold for PP1. Another missense variant, c.49C>G (p.Leu17Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP3.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248886	SCV001422566	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Leu17His variant in HNF1A has been reported in 2 individuals with maturity-onset diabetes of the young, segregated with disease in 2 affected relatives from 1 family (PMID: 21683639, 26479152), and has been identified in 0.0065% (1/15378) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1480672278). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu17His variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876298	SCV002174128	uncertain significance	not provided	2021-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with histidine at codon 17 of the HNF1A protein (p.Leu17His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with maturity onset diabetes of the young (PMID: 21683639). ClinVar contains an entry for this variant (Variation ID: 972749). 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. 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	RCV002464417	SCV002605552	likely pathogenic	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 rs1480672278 with MODY3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226452	SCV003922730	uncertain significance	not specified	2023-03-12	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.50T>A (p.Leu17His) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal domain (IPR006899) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247862 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.50T>A has been reported in the literature in individuals affected with features of HNF1A-MODY (Maturity Onset Diabetes Of The Young 3) (example, PMID: 26479152, 18003757, 21683639). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (ClinGen Monogenic Diabetes Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.