ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.481G>A (p.Ala161Thr)

gnomAD frequency: 0.00004  dbSNP: rs201095611
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Total submissions: 3
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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 RCV001248896 SCV001422577 uncertain significance Maturity-onset diabetes of the young type 3 2020-01-22 criteria provided, single submitter curation The p.Ala161Thr variant in HNF1A has not been previously reported in individuals with maturity-onset diabetes of the young and has been identified in 0.02% (20/113638) of European (non-Finnish) chromosomes, 0.007% (2/30616) of South Asian chromosomes, and 0.003% (1/34584) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201095611). 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, while the clinical significance of the p.Ala161Thr variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BA1, PP3 (Richards 2015).
Fulgent Genetics, Fulgent Genetics RCV002499436 SCV002803890 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 2024-03-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002570391 SCV003286021 uncertain significance not provided 2024-09-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 161 of the HNF1A protein (p.Ala161Thr). This variant is present in population databases (rs201095611, gnomAD 0.02%). This missense change has been observed in individuals with HNF1A-related conditions (PMID: 9754819, 21224407, 23517481, 23869231, 32041611, 34789499). ClinVar contains an entry for this variant (Variation ID: 972757). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 32910913). This variant disrupts the p.Ala161 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been observed in individuals with HNF1A-related conditions (PMID: 23517481), which suggests that this may be a clinically significant amino acid residue. 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.

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