ClinVar Miner

Submissions for variant NM_000545.6(HNF1A):c.1165T>G (p.Leu389Val) (rs115080759)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000445458 SCV000537089 likely benign Monogenic diabetes 2018-01-26 criteria provided, single submitter research ACMG criteria: PP3 (5 predictors), BP4 (4 predictors), BS2 (17 cases and 16 controls in T2DM, 169 hets in gnomAD)=likely benign
GeneDx RCV000835062 SCV000976842 likely benign not provided 2017-12-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Mendelics RCV000988923 SCV001138844 likely benign Maturity-onset diabetes of the young, type 3 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000121197 SCV001477047 benign not specified 2020-07-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121197 SCV001623244 likely benign not specified 2021-05-14 criteria provided, single submitter clinical testing Variant summary: HNF1A c.1165T>G (p.Leu389Val) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 284186 control chromosomes, predominantly at a frequency of 0.0063 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 252 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1165T>G has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (Bellanne_Chantelot_2008, Jeannot_2010, Flannick_2013) as well as in healthy controls (Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. Two functional studies reported this variant results in reduced transcriptional activity in cells (Najmi_2016, Juszczak_2018). Four ClinVar submitters (evaluation after 2014) cite the variant as benign (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000835062 SCV001718786 benign not provided 2020-11-14 criteria provided, single submitter clinical testing
ITMI RCV000121197 SCV000085367 not provided not specified 2013-09-19 no assertion provided reference population

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