ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.498T>A (p.Cys166Ter)

dbSNP: rs1555815393
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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 RCV004568336 SCV005050188 likely pathogenic Monogenic diabetes 2024-05-09 reviewed by expert panel curation The c.498T>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 166 (p.(Cys166Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 5 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 in gnomAD v2.1.1 (PM2_Supporting). It was identified in two 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 (ClinVar ID: 520675). In summary, c.498T>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting).
Ambry Genetics RCV002334036 SCV002642291 pathogenic Maturity onset diabetes mellitus in young 2017-11-16 criteria provided, single submitter clinical testing The p.C166* pathogenic mutation (also known as c.498T>A), located in coding exon 5 of the HNF4A gene, results from a T to A substitution at nucleotide position 498. This changes the amino acid from a cysteine to a stop codon within coding exon 5. 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002334036 SCV003804749 likely pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1555815393 in MODY, yet.

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