ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.981G>A (p.Trp327Ter)

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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 RCV004797990 SCV005420265 pathogenic Monogenic diabetes 2024-11-27 reviewed by expert panel curation The c.981G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 327 (p.(Trp327Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual 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. This individual did have a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative and persistent C peptide) (PP4_Moderate; PMID:16731861; internal lab contributors). This variant segregated with diabetes with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.981G>A meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting, PP4_Moderate.
Geisinger Clinic, Geisinger Health System RCV002285541 SCV002562120 pathogenic Maturity-onset diabetes of the young type 3 2022-08-02 criteria provided, single submitter research PVS1, PM2, PP4
Ambry Genetics RCV002373066 SCV002691999 pathogenic Maturity onset diabetes mellitus in young 2021-01-14 criteria provided, single submitter clinical testing The p.W327* pathogenic mutation (also known as c.981G>A), located in coding exon 8 of the HNF4A gene, results from a G to A substitution at nucleotide position 981. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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