Submissions for variant NM_000545.8(HNF1A):c.467C>T (p.Thr156Met)

gnomAD frequency: 0.00003  dbSNP: rs150513055

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030503	SCV000053174	likely pathogenic	Maturity-onset diabetes of the young type 3	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174361	SCV001337499	uncertain significance	Monogenic diabetes	2018-07-13	criteria provided, single submitter	research	ACMG criteria: PP3 (REVEL score 0.786 + 10 predictors), PM1 (DNA binding domain), BS1 (0.023% in South Asian), Note: 2 controls and 0 cases in T2D= VUS; but email from Kevin Collcough uses BA1 for variant being 1/2200 in South Asians (0.045% heterozygote frequency) which would make the variant benign; given all of this data we will leave variant as VUS
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001174361	SCV001422649	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Thr156Met variant in HNF1A has been reported in one individual with Monogenic Diabetes in ClinVar (Variation ID: 36822), and has been identified in 0.01960% (6/30616) of South Asian chromosomes and 0.01129% (4/35434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150513055). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36822). 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.Thr156Met variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513266	SCV003503956	uncertain significance	not provided	2024-08-02	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 156 of the HNF1A protein (p.Thr156Met). This variant is present in population databases (rs150513055, gnomAD 0.02%). This missense change has been observed in individual(s) with diabetes, hypoalphalipoproteinemia and/or maturity-onset diabetes of the young (PMID: 31291970, 33324081, 35460704, 36208030). ClinVar contains an entry for this variant (Variation ID: 36822). 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 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.
Fulgent Genetics, Fulgent Genetics	RCV005003406	SCV005632357	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	2024-01-25	criteria provided, single submitter	clinical testing