Submissions for variant NM_000545.8(HNF1A):c.1576G>A (p.Asp526Asn)

gnomAD frequency: 0.00002  dbSNP: rs1315721381

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004699128	SCV005201065	uncertain significance	Monogenic diabetes	2024-08-01	reviewed by expert panel	curation	The c.1576G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of aspartic acid to asparagine at codon 526 (p.(Asp526Asn)) of NM_000545.8. This variant was identified in an individual who was normoglycemic at 70 years old, and the expected penetrance for HNF1A-monogenic diabetes is 95% by age 70 (BS2; internal lab contributors). Additionally it was identified in the homozygous state in an individual not diagnosed with diabetes until the age of 62. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.805, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). The Grpmax filtering allele frequency of the c.1576G>A variant in gnomAD v2.1.1 is 0.00001123, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. While studies exploring the effect of this variant on protein function have been performed, these studies were conflicting, with cell line showing >75% activity and one cell one showing activity between 40% and 75%, and BS3 cannot be applied (PMID: 32910913). This variant was identified in at least 7 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 (ClinVar: 562466, internal lab contributors). Another missense variant, c.1576G>T p.Asp526Tyr, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1576G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS2, PP3, PP4.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248947	SCV001422726	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Asp526Asn variant in HNF1A has been reported in 1 European individual with MODY (PMID: 18003757), but has been identified in 0.005% (1/18390) of East Asian chromosomes and 0.004% (4/113566) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar as Likely Pathogenic by Gharavi Laboratory,Columbia University (Variation ID#: 562466). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp526Asn variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282325	SCV002570645	uncertain significance	not specified	2022-07-21	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1576G>A (p.Asp526Asn) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251254 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1576G>A has been reported in the literature in individuals referred for genetic testing for MODY3 (example, Bellane-Chantelot_2008), in patients with a reported diagnosis of MODY (example, Flannick_2013), as a VUS in settings of multigene panel testing for dyslipedemia and metabolic disorders (example, Dron_2020), in cohorts of individuals with Type 2 Diabetes (example, Bonnefond_2020), and as a variant observed in the Norway diagnostic registry that underwent a re-classification from pathogenic to VUS/likely benign (example, Althari_2020). At least one publication reports experimental evidence evaluating an impact on protein function (example, Althari_2020). The most pronounced variant effect results in impaired transactivation activity in HeLa (50%) and INS-1 cells (80%) using Luciferase assays with no significant impact on DNA binding ability and nuclear translocation in vitro. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002485582	SCV002783420	uncertain significance	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	2022-03-15	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000681952	SCV000809440	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research