ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.232C>T (p.Arg78Trp)

gnomAD frequency: 0.00001  dbSNP: rs780813696
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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 RCV003234562 SCV003932665 uncertain significance Monogenic diabetes 2023-05-27 reviewed by expert panel curation The c.232C>T variant in the HNF4A gene causes an amino acid change of arginine to tryptophan at codon 78 (p.Arg78Trp) of NM_175914.5. This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the number of cases is less the MDEP threshold of 4 cases for PS4_Moderate. This variant is located within the DNA binding domain (codons 37-113) which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.832, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information and age of diagnosis over 35 (internal lab contributors). In summary, c.232C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PM1_Supporting, PM2_Supporting PP3.
Athena Diagnostics RCV000517196 SCV000613651 uncertain significance not specified 2016-08-15 criteria provided, single submitter clinical testing
GeneDx RCV001755765 SCV001986071 uncertain significance not provided 2023-11-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18829458, 35118593, 32583173, 35052457, 21105491)
Fulgent Genetics, Fulgent Genetics RCV002481674 SCV002783015 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 2021-11-15 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003148764 SCV003804613 uncertain significance 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 rs780813696 in MODY, yet.

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