Submissions for variant NM_000545.8(HNF1A):c.827C>G (p.Ala276Gly)

gnomAD frequency: 0.00003  dbSNP: rs137853245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001248911	SCV002520656	likely pathogenic	Monogenic diabetes	2022-05-03	reviewed by expert panel	curation	The c.827C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 276 (p.(Ala276Gly)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant also is predicted to be deleterious by computational evidence, with a REVEL score of 0.901, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant has a minor allele frequency of 0.000007816 in the gnomAD v2.1.1 European non-Finnish population and one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributor). Another missense variant, c.827C>A (p.Ala276Asp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala276Gly (PM5_Supporting). In summary, c.827C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP3, PM2_Supporting, PS4_Moderate, PP4_Moderate, PM5_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030513	SCV000053184	likely pathogenic	Maturity-onset diabetes of the young type 3	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
GeneDx	RCV000441328	SCV000521028	likely pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	Reported in association with MODY in published literature (PMID: 18003757, 22432796); detailed patient clinical information not provided; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24097065, 27899486, 22432796, 33363396, 36208030, 18003757, 12453420)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248911	SCV001422646	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Ala276Gly variant in HNF1A has been reported in 2 individuals with Monogenic Diabetes (PMID: 18003757, 22432796), and has been identified in 0.004101% (1/24384) of African chromosomes and 0.0007816% (1/127936) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137853245). This variant has also been reported in 1 individual without diabetes (PMID: 24097065). 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 (Variation ID: 36832). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant causing a different amino acid change at the same position, p.Ala276Asp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 14945). Multiple variants in the same region as p.Ala276Gly have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 447504, 14931, 447503, 449403, 265193). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM5_Supporting, PS4_Supporting, PM1_Supporting (Richards 2015).
Revvity Omics, Revvity	RCV000441328	SCV003808681	likely pathogenic	not provided	2023-04-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030513	SCV004040826	likely pathogenic	Maturity-onset diabetes of the young type 3	2023-01-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007900	SCV005634472	likely 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	2024-02-06	criteria provided, single submitter	clinical testing