chr12-120993591-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PS4PP1_StrongPP4_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID:32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>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 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA214311/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HNF1A | NM_000545.8 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 10 | ENST00000257555.11 | NP_000536.6 | |
| HNF1A | NM_001306179.2 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 10 | NP_001293108.2 | ||
| HNF1A | NM_001406915.1 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 9 | NP_001393844.1 | ||
| HNF1A | XM_024449168.2 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 9 | XP_024304936.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HNF1A | ENST00000257555.11 | c.598C>T | p.Arg200Trp | missense_variant | Exon 3 of 10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461866Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727232
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Published functional studies show possible interference with protein localization; however, proper localization does not appear to be entirely eliminated (Bjrkhaug et al., 2005); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28012402, 29927023, 33046911, 16274290, 12453420, 9754819, 22060211, 17440016, 24014008, 34789499, 28410371, 33852230, 34440499, 36208030, 36504295, 35796342, 12050210) -
This variant disrupts the p.Arg200 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15522234, 15841481, 16274290, 30663027; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt HNF1A protein function. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the HNF1A protein (p.Arg200Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9754819, 22060211, 33046911). ClinVar contains an entry for this variant (Variation ID: 36824). -
The HNF1A c.598C>T; p.Arg200Trp variant (rs193922598, ClinVar Variation ID: 36824) is reported in the literature in numerous individuals suspected of or diagnosed with MODY (Breidbart 2021, Campos 2022, Chevre 1998, Colclough 2022, Ma 2020, Mirshashi 2022, Sahu 2007). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.599G>A, p.Arg200Gln) have been reported in individuals with MODY and are considered pathogenic (Mirshashi 2022). Functional analyses of the variant protein demonstrate reduced transactivation activity in HeLa cells (27% of WT), but INS1 cells show only a slight reduction in activity (84% of WT); additionally, DNA binding activity and protein expression were shown to be reduced (Kavitha 2023). Computational analyses predict that this variant is deleterious (REVEL: 0.775). Based on available information, this variant is considered to be pathogenic. References: Breidbart E et al. Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry. J Pediatr Endocrinol Metab. 2021 Apr 13;34(5):633-638. PMID: 33852230. Campos Franco P et al. Clinical and genetic characterization and long-term evaluation of individuals with maturity-onset diabetes of the young (MODY): The journey towards appropriate treatment. Diabetes Res Clin Pract. 2022 May;187:109875. PMID: 35472491. Chèvre JC et al. Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. Diabetologia. 1998 Sep;41(9):1017-23. PMID: 9754819. Colclough K et al. Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young. Diabetes. 2022 Mar 1;71(3):530-537. PMID: 34789499. Kavitha B et al. Molecular characterization and re-interpretation of HNF1A variants identified in Indian MODY subjects towards precision medicine. Front Endocrinol (Lausanne). 2023 Jun 16;14:1177268. PMID: 37396188. Ma Y et al. New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population. BMJ Open Diabetes Res Care. 2020 Mar;8(1):e000745. PMID: 32238361. Mirshahi UL et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. PMID: 36257325. Sahu RP et al. Etiology of early-onset type 2 diabetes in Indians: islet autoimmunity and mutations in hepatocyte nuclear factor 1alpha and mitochondrial gene. J Clin Endocrinol Metab. 2007 Jul;92(7):2462-7. doi: 10.1210/jc.2006-2467. Epub 2007 Apr 17. PMID: 17440016. -
This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in significant loss of nuclear localization of the HNF-1alpha protein (PMID: 16274290). The variant is located in a region that is considered important for protein function and/or structure. -
Maturity-onset diabetes of the young type 3 Pathogenic:2
PS4, PP1_strong, PM2, PM5, PP3, PP4 -
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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
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Monogenic diabetes Pathogenic:1
The c.598C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 200 (p.(Arg200Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.775, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.599G>A, p.(Arg200Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg200Trp has a greater Grantham distance (PM5). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; PMID: 32238361). This variant was identified in at least ten unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 17440016, 9754819, 29927023, 32238361; internal lab contributors). Lastly, this variant segregated with diabetes, with five informative meioses in five families with MODY (PP1_Strong; internal lab contributors). In summary, c.598C>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 9/30/2021): PP1_Strong, PM2_Supporting, PP3, PS4, PP4_Moderate, PM5. -
Maturity onset diabetes mellitus in young Pathogenic:1
Variant summary: HNF1A c.598C>T (p.Arg200Trp) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251336 control chromosomes (gnomAD). c.598C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 and has been documented to co-segregate with disease in affected families (e.g. Chevre_1998, Frayling_2001, Barrio_2002, Sahu_2007, Yorifuji_2012, Flannick_2013, Docena_2014, Bonnefond_2020, Ma_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant causes a defect in nuclear import which is expected to lead to altered gene activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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