ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.844G>A (p.Asp282Asn)

gnomAD frequency: 0.00001  dbSNP: rs145902391
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV000445391 SCV005367845 uncertain significance Monogenic diabetes 2024-09-26 reviewed by expert panel curation The c.844G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to asparagine at codon 282 (p.(Asp282Asn)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax minor filtering allele frequency of 0.000003000 (equal to the MDEP threshold of 0.000003), however, it has 3 copies in the European non-Finnish population (over the MDEP threshold of 2); therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant has a REVEL score of 0.42, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to a lack of clinical information (PMID: 27913849). In summary, c.844G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): no criteria met.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV000445391 SCV000537114 uncertain significance Monogenic diabetes 2016-02-03 criteria provided, single submitter research ACMG Criteria: PP3, BP4
Athena Diagnostics RCV000517930 SCV000613663 uncertain significance not specified 2017-03-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002446763 SCV002680759 uncertain significance Maturity onset diabetes mellitus in young 2020-01-06 criteria provided, single submitter clinical testing The p.D282N variant (also known as c.844G>A), located in coding exon 8 of the HNF4A gene, results from a G to A substitution at nucleotide position 844. The aspartic acid at codon 282 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in one antibody positive individual in the Norwegian Childhood Diabetes Registry (Johansson BB et al. Diabetologia, 2017 04;60:625-635). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002481356 SCV002792234 uncertain significance Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 2021-07-07 criteria provided, single submitter clinical testing

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