ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.511C>G (p.Arg171Gly)

dbSNP: rs1057520291
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003493884 SCV004242377 likely pathogenic Monogenic diabetes 2024-01-28 reviewed by expert panel curation The c.511C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 171 (p.(Arg171Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.888, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 26853433 and 31291970, internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, 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 is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.511C>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 2.1.0, approved 8/11/2023): PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV001895710 SCV002155501 pathogenic not provided 2021-10-13 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 26853433). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 19336507, 29439679; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 171 of the HNF1A protein (p.Arg171Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.
Molecular Genetics, Madras Diabetes Research Foundation RCV002051968 SCV002318397 pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter clinical testing

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