Submissions for variant NM_000545.8(HNF1A):c.1573A>T (p.Thr525Ser)

gnomAD frequency: 0.00001  dbSNP: rs759717253

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825937	SCV000967422	uncertain significance	not specified	2020-10-05	criteria provided, single submitter	clinical testing	The p.Thr525Ser variant in HNF1A has been reported in one individual with MODY (Bellanne-Chantelot 2008 PMID: 18003757; dbSNP rs759717253). It has also been identified in 0.009% (11/128938) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 654702). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr525Ser variant is uncertain. ACMG/AMP criteria applied: none.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248995	SCV001422839	uncertain significance	Maturity-onset diabetes of the young type 1	2020-01-22	criteria provided, single submitter	curation	The p.Thr525Ser variant in HNF1A has been reported in 1 individual with MODY (PMID: 18003757), but has been identified in 0.0085% (11/128938) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759717253). 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.Thr525Ser variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Institute of Experimental Endocrinology, Slovak Academy of Sciences	RCV001527412	SCV001738408	uncertain significance	Maturity-onset diabetes of the young type 3	2021-04-16	criteria provided, single submitter	research	In silico tools predict pathogenic effect on HNF1 alpha function (REVEL 0.83), on the other side, this variant was observed also in the gnomAD database with frequency 0.00003 (2 heterozygots from 34 000 subjects of European non-Finish origin). Based on this information, we classified the variant as of unknown significance (VUS).
Fulgent Genetics, Fulgent Genetics	RCV002495193	SCV002793856	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	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002538236	SCV003462612	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 525 of the HNF1A protein (p.Thr525Ser). This variant is present in population databases (rs759717253, gnomAD 0.009%). This missense change has been observed in individual(s) with MODY (PMID: 18003757, 33046911). ClinVar contains an entry for this variant (Variation ID: 667246). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002538236	SCV004132115	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	HNF1A: PM5:Supporting