ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.734G>T (p.Gly245Val)

dbSNP: rs193922603
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002250357 SCV002520653 uncertain significance Monogenic diabetes 2022-05-02 reviewed by expert panel curation The c.734G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to valine at codon 245 (p.Gly245Val) 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 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative antibodies, and low hsCRP; HNF4A not tested, but low hsCRP is specific to HNF1A vs. HNF4A) (PP4_Moderate; PMID: 30181854). Another missense variant, c.733G>A (p.Gly245Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.734G>T 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, PP4_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030510 SCV000053181 likely pathogenic Maturity-onset diabetes of the young type 3 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Athena Diagnostics RCV000993273 SCV001146110 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing

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