Submissions for variant NM_000545.8(HNF1A):c.827C>A (p.Ala276Asp)

dbSNP: rs137853245

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001248962	SCV002520642	pathogenic	Monogenic diabetes	2022-04-18	reviewed by expert panel	curation	The c.827C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to aspartic acid at codon 276 (p.(Ala276Asp)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individuals with 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 sulfonylurea (PP4_Moderate, internal lab contributors). Another missense variant, c.827C>G (p.Ala276Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Also, the variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated abnormal nuclear localization, DNA binding less than 40% of wildtype, and normal transactivation (PS3_Supporting; PMID:12574234). This variant is absent from the gnomAD European non-Finnish population, but two copies are present in the African population; therefore PM2_Supporting cannot be applied. This variant was identified in at least 12 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 12574234, internal lab contributors). In summary, c.827C>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): PP1_Strong, PP4_Moderate, PP3, PM1_Supporting, PM5_Supporting, PS3_Supporting.
GeneDx	RCV000521190	SCV000617535	likely pathogenic	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The A276D variant has been reported previously in association with MODY (Bjørkhaug et al., 2003; Bellanné-Chantelot et al., 2008). The variant is observed in 1/8770 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). A276D is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (A276G) and in nearby residues (R271W/G/Q, R272S/H, K273N, K280E, L281P) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248962	SCV001422762	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Ala276Asp variant in HNF1A has been reported in at least 2 individuals with monogenic diabetes (PMID: 18003757, 12574234), and has been identified in 0.01% (2/15696) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137853245). 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 in ClinVar as likely pathogenic and pathogenic (Variation ID#: rs137853245). In vitro functional studies provide some evidence that the p.Ala276Asp variant may slightly impact protein function (PMID: 12574234). However, these types of assays may not accurately represent biological function. 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, PS3_supporting, PS4_supporting (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV000521190	SCV002070471	likely pathogenic	not provided	2021-06-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.827C>A, in exon 4 that results in an amino acid change, p.Ala276Asp. This sequence change has been described in gnomAD with a low frequency of 0.013% in the African/African American sub-population (dbSNP rs137853245). The p.Ala276Asp change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Ala276Asp substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This particular sequence change has been previously reported in an individual with HNF1A-related diabetes (PMID: 12574234). A different amino acid change at this same positon (p.Ala276Gly) has also been reported in individuals with HNF1A-related diabetes (PMIDs: 18003757, 24097065, 27899486). Functional studies have demonstrated that the p.Ala276Asp variant may slightly impact protein function (PMID: 12574234). In summary this sequence change has been interpreted as likely pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002254266	SCV002525664	pathogenic	Hyperinsulinism due to HNF1A deficiency	2020-01-31	criteria provided, single submitter	clinical testing	The p.Ala276Asp variant replaces the alanine with aspartic acid at position 276 of the protein. This variant has previously been reported as pathogenic in two individuals diagnosed with MODY (PMID: 12574234, 24097065). The p.Ala276Asp is not a common variant in the general population (observed in 2 of 248,546 alleles in the Genome Aggregation Database). This variant has been interpreted as likely pathogenic by an outside laboratory (ClinVar Variation ID: 29984). In silico tools predict this alteration is damaging (DANN, MutationTaster, SIFT). Further supporting pathogenicity, a different missense change at the same residue (p.Ala276Gly) has been reported in an individual with MODY (NBK500456).
OMIM	RCV000016083	SCV000036351	pathogenic	Maturity-onset diabetes of the young type 3	2003-02-01	no assertion criteria provided	literature only