Submissions for variant NM_000545.8(HNF1A):c.1424C>T (p.Pro475Leu)

dbSNP: rs193922580

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001248915	SCV005201063	uncertain significance	Monogenic diabetes	2024-08-01	reviewed by expert panel	curation	The c.1424C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 475 (p.(Pro475Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.751, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, 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) (PP4; internal lab contributors). This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 18811724, 23674172, internal lab contributors). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2: internal lab contributors). The frequency of the c.1424C>T variant in gnomAD v2.1.1 falls between the ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.1424C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PP4, BS2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387733	SCV000053151	uncertain significance	not specified	2023-09-26	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1424C>T (p.Pro475Leu) 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 5.2e-05 in 250026 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), suggesting that the variant may be benign. c.1424C>T has been reported in the literature in several individuals affected with diabetes (e.g., Plengvidhya_2009, Billings_2022), however without strong evidence for causality (e.g., lack of co-segregation data) in all cases. The variant was also identified in several unaffected control individuals (e.g., Billings_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in moderate defects in BCL2L1 transactivation (approx. 28% reduction relative to wildtype) as well as defects in regulation of cell cycle transitions (e.g., Sujjitjoon_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 18811724, 32684311). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: three submitters classified the variant as VUS, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Athena Diagnostics	RCV000993264	SCV001146099	uncertain significance	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248915	SCV001422651	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Pro475Leu variant in HNF1A has been reported in at least 2 individuals (including 1 Thai individual) with Monogenic Diabetes (PMID: 18811724, 23348805), and has been identified in 0.09954% (10/10046) of Ashkenazi Jewish chromosomes and 0.002659% (3/112840) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922580). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar and as a VUS in the literature (Variation ID: 36801; PMID: 27080136). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro475Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000993264	SCV001605983	likely benign	not provided	2024-05-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390124	SCV002702712	uncertain significance	Maturity onset diabetes mellitus in young	2021-01-20	criteria provided, single submitter	clinical testing	The p.P475L variant (also known as c.1424C>T), located in coding exon 7 of the HNF1A gene, results from a C to T substitution at nucleotide position 1424. The proline at codon 475 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a Thai subject with type 2 diabetes (Plengvidhya N et al. Clin Endocrinol (Oxf), 2009 Jun;70:847-53). This variant has been noted to have reduced transactivation activity and affected cell cycle and growth (Sujjitjoon J et al. Biochem Biophys Res Commun, 2020 Aug;529:826-833). 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 alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005007896	SCV005634501	uncertain significance	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	2024-04-18	criteria provided, single submitter	clinical testing