Submissions for variant NM_000545.8(HNF1A):c.872C>G (p.Pro291Arg)

dbSNP: rs193922606

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001248913	SCV002765153	uncertain significance	Monogenic diabetes	2022-08-05	reviewed by expert panel	curation	The c.872C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 291 (p.(Pro291Arg)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009402, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). 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 (internal lab contributors). Two other missense variants, c. 871C>A, p. Pro291Thr and c.871C>G, p.Pro291Ala, have been classified as VUS; therefore, PM5 will not be applied. Lastly, this variant has a REVEL score of 0.4189, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.872C>G meets the criteria to be classified as variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): BS1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030514	SCV000053185	likely pathogenic	Maturity-onset diabetes of the young type 3	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248913	SCV001422648	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Pro291Arg variant in HNF1A has been reported in at least one individual with Monogenic Diabetes in ClinVar (Variation ID: 36833), and has been identified in 0.03450% (8/23188) of African chromosomes and 0.0008106% (1/123362) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922606). This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36833). 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. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Another variant at the same position, p.Pro291Ser, has been reported benign in ClinVar (Variation ID: 447505). In summary, the clinical significance of the p.Pro291Arg variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV003456361	SCV004184279	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	HNF1A: PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV003456361	SCV005825028	uncertain significance	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 291 of the HNF1A protein (p.Pro291Arg). This variant is present in population databases (rs193922606, gnomAD 0.03%). This missense change has been observed in individual(s) with hyperglycemia (PMID: 34202200). ClinVar contains an entry for this variant (Variation ID: 36833). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. 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.