chr12-120997504-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000545.8(HNF1A):c.1340C>T(p.Pro447Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. P447P) has been classified as Likely benign.
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1340C>T | p.Pro447Leu | missense_variant | 7/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1340C>T | p.Pro447Leu | missense_variant | 7/10 | ||
HNF1A | XM_024449168.2 | c.1340C>T | p.Pro447Leu | missense_variant | 7/9 | ||
HNF1A | NM_001406915.1 | c.1309+762C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1340C>T | p.Pro447Leu | missense_variant | 7/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249186Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134986
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459660Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726138
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2023 | Published functional studies demonstrate a damaging effect: loss of trans-activation activity and dominant negative effect (Vaxillaire et al., 1999; Najmi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20393147, 16496320, 11058894, 24915262, 29207974, 34496959, 12530534, 26646800, 30121369, 12574234, 28701371, 21224407, 17937063, 17573900, 29927023, 18838325, 11296231, 8945470, 9075819, 32041611, 10585442, 27899486, 36227502) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 12530534). 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) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 14928). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the HNF1A protein (p.Pro447Leu). - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 12, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed reduction in transcription activity (PMID: 24915262, 10585442, 12530534). - |
Maturity onset diabetes mellitus in young Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs137853236 with MODY3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2021 | Variant summary: HNF1A c.1340C>T (p.Pro447Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249186 control chromosomes (gnomAD). c.1340C>T has been reported in the literature in multiple individuals affected with or suspected of Maturity Onset Diabetes of the Young 3 (example: Yamagata_1996, Estalella_2007. Yorifuji_2018) . These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant was found to have reduced DNA binding and transcriptional activity (example: Thomas_2002, Najmi_2017). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Dec 31, 2021 | The c.1340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 447 (p.(Pro447Leu)) of NM_000545.8. This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY ([MODY probability calculator result <50%/HNF4A not tested) (PS2_Supporting; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro447Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMIDs: 27899486, 12530534, 10585442, 32910913, 32910913). This variant was identified in 11 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 15 informative meioses in families with MODY (PP1_Strong; internal lab contributors), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.1340C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PS4, PP1_Strong, PP3, PP4, PS2_Supporting, PM2_Supporting, PS3_Moderate. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at