ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.326+1G>T

dbSNP: rs2135820424
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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 RCV002260404 SCV002540110 pathogenic Monogenic diabetes 2022-06-10 reviewed by expert panel curation The c.326+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 1 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent positive C- peptide) (PP4_Moderate; internal lab contributors). The c.326+1G>A and c.326+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>T has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). Lastly, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.326+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/21): PVS1, PS1_Supporting, PP4_Moderate, PM2_Supporting.
Genetic Services Laboratory, University of Chicago RCV001817891 SCV002067322 pathogenic not provided 2019-04-30 criteria provided, single submitter clinical testing

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