ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.724del (p.Val242fs)

dbSNP: rs1555816642
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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 RCV003493617 SCV004242373 pathogenic Monogenic diabetes 2024-01-22 reviewed by expert panel curation The c.724del variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 242 in NM_175914.5, adding 39 novel amino acids before encountering a stop codon (p.(Val242Cysfs*39)). This variant, located in biologically-relevant exon 7 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 is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.724del 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.
Athena Diagnostics RCV000517835 SCV000613660 pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002376954 SCV002672473 pathogenic Maturity onset diabetes mellitus in young 2018-10-20 criteria provided, single submitter clinical testing The c.724delG pathogenic mutation, located in coding exon 7 of the HNF4A gene, results from a deletion of one nucleotide at nucleotide position 724, causing a translational frameshift with a predicted alternate stop codon (p.V242Cfs*39). This mutation was reported in a maturity-onset diabetes of the young family (Colclough K et al. Hum. Mutat., 2013 May;34:669-85). In addition to the clinical data presented in the literature, 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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