Submissions for variant NM_000545.8(HNF1A):c.1849G>A (p.Val617Ile)

gnomAD frequency: 0.00006  dbSNP: rs146855738

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002250374	SCV002520649	benign	Monogenic diabetes	2022-05-02	reviewed by expert panel	curation	The c.1849G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to isoleucine at codon 617 (p.(Val617Ile)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003429, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant also was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (internal lab contributors) (BS2). 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 two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold, and PM2_Supporting is not met (PMID: 12488962, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 12488962). Transactivation activity (COS-7 cells) was 63% of wildtype, which was between ClinGen MDEP thresholds for PS3_Supporting and BS3_Supporting (PMID: 12488962). In summary, c.1849G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BS1, BS2, PP4.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248942	SCV001422721	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Val617Ile variant in HNF1A has been reported in 2 Japanese individuals with MODY (PMID: 12488962) and another variant of unknown significance in cis, but has been identified in 0.007% (9/128784) of European (non-Finnish) chromosomes and 0.004% (1/24946) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146855738). In vitro functional studies provide some evidence that the p.Val617Ile variant may slightly impact protein function (PMID: 12488962). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val617Ile variant is uncertain. ACMG/AMP Criteria applied: BS1, PS3_supporting (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV005012688	SCV005634528	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	2024-06-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001573527	SCV005775726	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 617 of the HNF1A protein (p.Val617Ile). This variant is present in population databases (rs146855738, gnomAD 0.007%). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 12488962). ClinVar contains an entry for this variant (Variation ID: 972765). 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 HNF1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573527	SCV001799531	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001573527	SCV001972358	uncertain significance	not provided		no assertion criteria provided	clinical testing