Submissions for variant NM_000545.8(HNF1A):c.392G>A (p.Arg131Gln)

dbSNP: rs753998395

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001796178	SCV002032344	pathogenic	Monogenic diabetes	2021-08-11	reviewed by expert panel	curation	The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID: 32910913 and PMID: 10585442) (PS3_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have 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). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248948	SCV001422727	pathogenic	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Arg131Gln variant in HNF1A has been reported in at least 15 individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 2 families (PMID: 24323243, 12442280, 22060211, 17937063, 18838325, 11315851, 9032114, 9287053, 18003757), but has been identified in 0.0009% (1/113698) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753998395). 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 pathogenic by Columbia University in ClinVar (Variation ID: 562373). In vitro functional studies provide some evidence that the p.Arg131Gln variant may slightly impact protein function (PMID: 27899486). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg131Gln variant is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 28410371). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on more affected individuals with the variant than expected, low frequency in the general population, location in a functional domain, and in vitro functional studies. ACMG/AMP Criteria applied: PS4, PM2, PM1, PP3, PP1, PS3_Supporting (Richards 2015).
GeneDx	RCV000681832	SCV001803365	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased target promoter activity compared to wildtype (PMID: 23607861); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24097065, 29927023, 28012402, 21761282, 34462253, 30586318, 25414397, 8945470, 27899486, 28410371, 11058894, 12442280, 18838325, 18513302, 27634015, 19754856, 30754156, 12453420, 17937063, 30754209, 23607861, 22060211, 34108472, 18003757, 36227502, 24323243)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464290	SCV002605480	pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs753998395 with MODY3.
Athena Diagnostics	RCV000681832	SCV002770448	pathogenic	not provided	2021-10-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features associated with this gene, including multiple de novo occurrences. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant shows reduced transcriptional activity compared to wildtype in multiple cell lines (PMID: 23607861, 27899486, 32910913). The variant is located in a region that is considered important for protein function and/or structure.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681832	SCV003293543	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 131 of the HNF1A protein (p.Arg131Gln). This variant is present in population databases (rs753998395, gnomAD 0.0009%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562373). 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) has been performed 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. Experimental studies have shown that this missense change affects HNF1A function (PMID: 27899486). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005010674	SCV005632354	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	2024-01-08	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681832	SCV000809307	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV001248948	SCV004024126	pathogenic	Maturity-onset diabetes of the young type 3		no assertion criteria provided	research