Submissions for variant NM_000545.8(HNF1A):c.245C>T (p.Thr82Met)

gnomAD frequency: 0.00006  dbSNP: rs568123980

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449764	SCV001653039	uncertain significance	not specified	2020-10-26	criteria provided, single submitter	clinical testing	The p.Thr82Met variant in HNF1A has been reported in at least 1 individual with early-onset and/or multiplex diabetes and 1 individual with type I diabetes (Yang 2006 PMID: 16834925, Yu 2019 PMID: 31264968). It has been identified in 0.005% (10/19468) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 this variant is uncertain. ACMG/AMP Criteria applied: PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001872002	SCV002115071	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the HNF1A protein (p.Thr82Met). This variant is present in population databases (rs568123980, gnomAD 0.05%). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 16834925, 23771925, 31264968). ClinVar contains an entry for this variant (Variation ID: 1120099). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001449764	SCV002766080	uncertain significance	not specified	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.245C>T (p.Thr82Met) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal domain (IPR006899) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 268808 control chromosomes (gnomAD), predominantly at a frequency of 0.00051 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.245C>T has been reported in the literature in individuals diagnosed with diabetes later than 50 years of age (Yang_2006), in an individual diagnosed with type 1 diabetes who had a negative family history for disease (Yu_2019), and in youths diagnosed with diabetes with unknown pedigrees (Pihoker_2013, Liu_2021). These reports 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 ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Revvity Omics, Revvity	RCV001872002	SCV003808682	uncertain significance	not provided	2021-11-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005005246	SCV005632348	uncertain significance	Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma	2024-03-04	criteria provided, single submitter	clinical testing