ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.1556C>T (p.Pro519Leu)

gnomAD frequency: 0.00001  dbSNP: rs749673816
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002260481 SCV002540107 pathogenic Monogenic diabetes 2024-10-25 reviewed by expert panel curation The c.1556C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 519 (p.(Pro519Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.828, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with at least 9 informative meioses in 7 families with MODY (PP1_Strong; PMID: 30293189, internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 32238361, 29758564, 30293189, internal lab contributors). 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 sulfonylurea-sensitive) (PP4_Moderate; internal lab contributors). In summary, c.1556C>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 9/30/21): PM2_Supporting, PP3, PS4, PP4, PP1_Strong.
Ambry Genetics RCV002400403 SCV002704379 uncertain significance Maturity onset diabetes mellitus in young 2015-08-30 criteria provided, single submitter clinical testing The p.P519L variant (also known as c.1556C>T), located in coding exon 8 of the HNF1A gene, results from a C to T substitution at nucleotide position 1556. The proline at codon 519 is replaced by leucine, an amino acid with similar properties. This variant was detected in a UK MODY3 family (Frayling TM et al, Diabetes 1997 Apr; 46(4):720-5). In cell functional assays, this variant showed a dominant-negative effect on the histone acetyltransferase activity of CBP and p/CAF (Soutoglou E et al, EMBO J. 2001 Apr; 20(8):1984-92). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics RCV002473361 SCV002770447 likely pathogenic not provided 2021-11-04 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant alters expression of target genes (PMID: 11296231, 32910913).
Fulgent Genetics, Fulgent Genetics RCV002502070 SCV002812058 likely pathogenic Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma 2022-01-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV002473361 SCV004564532 likely pathogenic not provided 2023-10-10 criteria provided, single submitter clinical testing The HNF1A c.1556C>T; p.Pro519Leu variant (rs749673816) is reported in the literature in several individuals and families affected with MODY (Frayling 1997, Kleinberger 2018, Ma 2020, Mirshahi 2022, Wang 2019). This variant is reported in ClinVar (Variation ID: 1693221) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.828). Functional analyses of the variant protein show increased binding to histone acetyltransferases and nuclear localization but decreased activity and protein expression (Althari 2020, Soutoglou 2001). Based on available information, this variant is considered to be likely pathogenic. References: Althari S et al. Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation. Am J Hum Genet. 2020 Oct 1;107(4):670-682. PMID: 32910913. Frayling TM et al. Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K. Diabetes. 1997 Apr;46(4):720-5. PMID: 9075818. Kleinberger JW et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018 Jun;20(6):583-590. PMID: 29758564. 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. Soutoglou E et al. Transcription factor-dependent regulation of CBP and P/CAF histone acetyltransferase activity. EMBO J. 2001 Apr 17;20(8):1984-92. PMID: 11296231. Wang X et al. Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young. Acta Diabetol. 2019 Mar;56(3):281-288. PMID: 30293189.
PreventionGenetics, part of Exact Sciences RCV004753547 SCV005356670 pathogenic HNF1A-related disorder 2024-08-02 no assertion criteria provided clinical testing The HNF1A c.1556C>T variant is predicted to result in the amino acid substitution p.Pro519Leu. This variant has been reported in multiple individuals and families with MODY type III (Frayling et al. 1997. PubMed ID: 9075818; Wang et al. 2018. PubMed ID: 30293189; Kleinberger et al. 2018. PubMed ID: 29758564; Ma et al. 2020. PubMed ID: 32238361; Supplementary Table 4, Colclough et al. 2022. PubMed ID: 34789499; Mirshahi et al. 2022. PubMed ID: 36257325) and has been interpreted as pathogenic by the ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1693221/). Functional studies showed decreased protein expression and transcriptional activity with increased binding to histone acetyltransferases and nuclear localization (Althari et al. 2020. PubMed ID: 32910913). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

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