ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.583-1G>A

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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 RCV004574960 SCV005050169 pathogenic Monogenic diabetes 2024-05-09 reviewed by expert panel curation The c.583-1G>A variant in the hepatocyte nuclear factor4-alpha gene, HNF4A, is predicted to remove a canonical splice acceptor site in intron 5 of NM_175914.5. This variant is predicted to cause skipping of biologically-relevant exon 6 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). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). In summary, c.583-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PP4, PM2_Supporting.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004796870 SCV005416962 pathogenic Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young criteria provided, single submitter clinical testing PM2_Supporting+PVS1+PP4

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