chr20-44419790-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP1_ModeratePP4_ModeratePP3PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA409107461/MONDO:0015967/085
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2020 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | 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. - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 30, 2024 | 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. - |
Maturity-onset diabetes of the young type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 29, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at