ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.733G>A (p.Gly245Arg)

dbSNP: rs2135841196
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002222077 SCV002499534 uncertain significance Monogenic diabetes 2022-04-12 reviewed by expert panel curation The c.733G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 245 (p.Gly245Arg) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Gly245Arg protein has normal DNA binding but ~55% of transactivation activity and ~55% of nuclear localization compared to wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 28653443). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50% and negative antibodies); however, HNF4A was not tested, and PP4 will not be applied (PMIDs: 19336507, 28653433). Another missense variant, c.734C>T (p.Gly245Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.733G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3.
Molecular Genetics, Madras Diabetes Research Foundation RCV002052028 SCV002318419 uncertain significance Maturity onset diabetes mellitus in young criteria provided, single submitter clinical testing

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