rs193922480
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_SupportingPM1_SupportingPS4PP4_ModeratePS2_ModeratePP3
This summary comes from the ClinGen Evidence Repository: The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID:28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID:28862987). In summary, c.931C>T 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, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214003/MONDO:0015967/085
Frequency
Consequence
NM_175914.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF4A | NM_175914.5 | c.931C>T | p.Arg311Cys | missense_variant | 8/10 | ENST00000316673.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF4A | ENST00000316673.9 | c.931C>T | p.Arg311Cys | missense_variant | 8/10 | 1 | NM_175914.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461164Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726872
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg311 amino acid residue in HNF4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10768098, 25414397, 26059258, 32533152, 36227502, 36257325). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 36365). This variant is also known as R324C. This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 22060211, 28862987, 35089870). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 311 of the HNF4A protein (p.Arg311Cys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 29417725, 28862987, 22060211) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 31, 2018 | - - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jul 28, 2024 | The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 28862987). In summary, c.931C>T 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, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting. - |
Maturity onset diabetes mellitus in young Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2022 | Variant summary: HNF4A c.931C>T (p.Arg311Cys) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. This variant is also referred as HNF4A c.997C>T (p.Arg333Cys). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248874 control chromosomes (gnomAD). c.931C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus (examples: Yorifuji_2012, Globa_2017, Johnson_2017, Carlson_2020, and Saint-Martin_2022). Other variants affecting the same amino acid residue (R311H/R311P/R311S) is associated with diabetes/MODY in HGMD. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at