Submissions for variant NM_175914.5(HNF4A):c.740T>C (p.Leu247Pro)

dbSNP: rs1555816654

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004699125	SCV005201073	pathogenic	Monogenic diabetes	2024-08-30	reviewed by expert panel	curation	The c.740T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 247 (p.(Leu247Pro)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and is predicted to be deleterious by computational evidence, with a REVEL score of 0.979, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23771925, internal lab contributors). 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, and response to low-dose SU ) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.733G>C 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): PS4, PP1_moderate, PP3, PP4_moderate, PM2_Supporting.
Genetic Services Laboratory, University of Chicago	RCV000502655	SCV000595154	likely pathogenic	Maturity-onset diabetes of the young type 1	2016-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001755742	SCV001986073	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in one patient with maturity onset diabetes of the young, however, family segregation and functional studies were not performed; please note that this variant is reported using alternate nomenclature L260P (Pihoker et al., 2013); This variant is associated with the following publications: (PMID: 23771925)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001755742	SCV005838100	uncertain significance	not provided	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 247 of the HNF4A protein (p.Leu247Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 23771925, 34789499). This variant is also known as c.779T>C p.L260P. ClinVar contains an entry for this variant (Variation ID: 435438). Invitae Evidence 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 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.