ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.1501+5G>C

dbSNP: rs1399164820
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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 RCV002250407 SCV002520643 uncertain significance Monogenic diabetes 2022-04-18 reviewed by expert panel curation The c.1501+5G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to impact splicing in intron 7 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.64 for donor loss, predicting that the variant disrupts the donor site of intron 7 of HNF1A (PP3). This variant was identified in an individual(s) with diabetes; however, the calculated MODY probability is <50%, and PP4 cannot be applied (internal lab contributors). In summary, c.1501+5G>C 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 9/30/21): PM2_Supporting, PP3.
Dept of Medical Genetics, AP-HP Sorbonne University, Pitié-Salpêtrière hospital RCV003329438 SCV004037068 likely pathogenic Maturity onset diabetes mellitus in young 2022-11-01 criteria provided, single submitter clinical testing minigene showed effect on RNA splicing: in-frame skipping of exon 7 (r.1310_1501del, p.Gly437_His500del) as main transcript; and retention of the first 42 bp of intron 7 (r.1501_1502ins42, p.His500_Ala501ins(14)). PS3 PM2
GeneDx RCV004591852 SCV005079190 uncertain significance not provided 2024-04-19 criteria provided, single submitter clinical testing Observed in an family with maturity-onset diabetes of the young in the published literature without additional clinical or segregation information (PMID: 23348805); Not observed at significant frequency in large population cohorts (gnomAD); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect; RNA studies demonstrate a damaging effect of exon skipping and intronic retention (42 bp) (Bouvet2023[Article]) Delphine Bouvet,Amlie Blondel,Jean-Madeleine de Sainte Agathe,Gwendoline Leroy,Ccile Saint-Martin,and Christine Bellann-Chantelot. (2023) Human Mutation. 2023 https://doi.org/10.1155/2023/6661013; This variant is associated with the following publications: (PMID: 23348805, Bouvet2023[Article])

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