ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.1061C>T (p.Thr354Met)

gnomAD frequency: 0.00006  dbSNP: rs757068809
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001249068 SCV001423016 uncertain significance Maturity-onset diabetes of the young type 3 2020-01-22 criteria provided, single submitter curation The p.Thr354Met variant in HNF1A has been reported in at least 5 individuals with MODY (PMID: 27913849, 11058894, 29207974, 18003757), but has been identified in 0.02% (6/35440) of Latino chromosomes and 0.009% (11/129110) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757068809). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr354Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PS4 (Richards 2015).
Molecular Genetics, Madras Diabetes Research Foundation RCV002051927 SCV002318387 likely pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002570392 SCV003244143 uncertain significance not provided 2025-01-22 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 354 of the HNF1A protein (p.Thr354Met). This variant is present in population databases (rs757068809, gnomAD 0.02%). This missense change has been observed in individuals with HNF1A-related conditions (PMID: 25414397, 29207974, 29439679, 32910913). ClinVar contains an entry for this variant (Variation ID: 972811). 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%. Experimental studies have shown that this missense change affects HNF1A function (PMID: 32910913, 37396188). 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.
GeneDx RCV002570392 SCV005078883 uncertain significance not provided 2023-11-08 criteria provided, single submitter clinical testing Published functional studies demonstrate slightly reduced transactivation activity, however, the consequences of this result remain unclear (PMID: 37396188, 32910913); The frequency of this variant in large population cohorts is higher than expected for disorder(s) associated with this gene (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21224407, 27072194, 11058894, Zubkova2017[Case Report], ZubkovaA2017[Case Report], 32910913, 37798422, 37327085, 27913849, 37396188, 29439679, 29207974, 25414397, 18003757)

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