Submissions for variant NM_175914.5(HNF4A):c.787G>C (p.Glu263Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003234589	SCV003932654	likely pathogenic	Monogenic diabetes	2023-05-27	reviewed by expert panel	curation	The c.787G>C variant in the HNF4A gene causes an amino acid change of glutamic acid to glutamine at codon 263 (p.Glu263Gln) of NM_175914.5. Functional studies demonstrated the p.Glu276Gln protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 30325586, 30191603). This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.789G>C p.Glu263Asp has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. This variant segregated with diabetes, with at least 5 informative meioses in 1 family with MODY (PP1_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and a family history of neonatal hyperglycemia and response to sulphonylurea) (PP4_Moderate; internal lab collaborator). In summary, c.787G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PS3_Supporting PM2_Supporting, PP1_Strong, PP3_Supporting, PP4_Moderate.
Geisinger Clinic, Geisinger Health System	RCV002285538	SCV002562112	likely pathogenic	Maturity-onset diabetes of the young type 1	2022-08-02	criteria provided, single submitter	research	PP1_Strong, PP4_Moderate, PM2, PP3, PS3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560914	SCV004298080	pathogenic	not provided	2023-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 263 of the HNF4A protein (p.Glu263Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF4A function (PMID: 10331424, 30191603, 30325586). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF4A protein function. ClinVar contains an entry for this variant (Variation ID: 1700660). This variant is also known as p.E276Q. This missense change has been observed in individuals with maturity-onset diabetes of the young (MODY) (PMID: 9243109, 36257325). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).