Submissions for variant NM_000545.8(HNF1A):c.812G>A (p.Arg271Gln)

gnomAD frequency: 0.00001  dbSNP: rs779184183

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222046	SCV002499557	pathogenic	Monogenic diabetes	2022-04-15	reviewed by expert panel	curation	The c.812G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 271 (p.(Arg271Gln) of NM_000545.8. This variant was identified in 19 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.945, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Arg271Gln protein has DNA binding 110% of wild type and transactivation 50-60% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 26853433). The p.Arg271Trp and p.Arg271Gly variants have been interpreted as pathogenic and likely pathogenic, respectively, by the MDEP. Arg271Gln has a lower Grantham distance than both and was used as the base variant to apply PM5, and therefore, PM5 will not be applied to Arg271Gln. In summary, c.814C>A 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 9/30/2021): PS4, PP1_Strong, PM1, PP3, PM2_Supporting, PP4_Moderate.
GeneDx	RCV000519064	SCV000617534	pathogenic	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (PMID: 26853433); 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: 17937063, 33852230, 12488961, 26997508, 29207974, 33538814, 34108472, 36208030, 36257325, 26853433, 9754819, 16274290)
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051863	SCV002318437	likely pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	clinical testing
Geisinger Clinic, Geisinger Health System	RCV002285353	SCV002562146	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PS4, PP1_Strong, PM1, PP3, PM2
Athena Diagnostics	RCV000519064	SCV002770450	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused significant reduction in transactivation activity (PMID: 26853433). The variant is located in a region that is considered important for protein function and/or structure.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002285353	SCV003925618	pathogenic	Maturity-onset diabetes of the young type 3	2023-04-28	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4, PP1_STR, PP4_MOD, PM2_SUP, PP3
Ambry Genetics	RCV002051863	SCV005601289	likely pathogenic	Maturity onset diabetes mellitus in young	2024-10-16	criteria provided, single submitter	clinical testing	The c.812G>A (p.R271Q) alteration is located in exon 4 (coding exon 4) of the HNF1A gene. This alteration results from a G to A substitution at nucleotide position 812, causing the arginine (R) at amino acid position 271 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/249024) total alleles studied. The highest observed frequency was 0.006% (1/18344) of East Asian alleles. This variant was reported in multiple individuals with diabetes onset younger than 35 years old, normal BMI, negative autoantibodies, an affected parent, and/or clinically suspected MODY (Tonooka, 2002; Stern, 2007; Radha, 2009; Balamurugan, 2016; Bitterman, 2016; Marchand, 2021). Two other alterations at the same codon, c.811C>T (p.R271W) and c.811C>G (p.R271G) have been detected in individuals with clinical features of MODY (Barrio, 2002; Malecki, 2005). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519064	SCV005836122	pathogenic	not provided	2024-10-21	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 271 of the HNF1A protein (p.Arg271Gln). This variant is present in population databases (rs779184183, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 2975864, 17937063, 26853433). ClinVar contains an entry for this variant (Variation ID: 449403). 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: 26853433). This variant disrupts the p.Arg271 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9754819, 12488961, 12574234, 15928245, 16249556, 21170474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV001175315	SCV001250632	pathogenic	Diabetes mellitus		no assertion criteria provided	research	PS1 PM2 PM5 PP3