Submissions for variant NM_000545.8(HNF1A):c.685C>G (p.Arg229Gly)

dbSNP: rs769086289

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810527	SCV002059975	likely pathogenic	Monogenic diabetes	2021-12-30	reviewed by expert panel	curation	The c.685C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 229 (p.(Arg229Gly)) of NM_000545.6. This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), one of whom also responded to low dose sulfonylurea treatment (PP4_Moderate; internal laboratory contributor). This variant is located within 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). Two other missense variants, c.686G>A(p.(Arg229Gln)) and c.686G>C (p.(Arg229Pro), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Finally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). In summary, c.685C>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 6/4/2021): (PP4_Moderate, PM1_Supporting, PM5_Strong, PM2_Supporting, PP3).
Labcorp Genetics (formerly Invitae), Labcorp	RCV005095226	SCV005836121	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 229 of the HNF1A protein (p.Arg229Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 23348805). ClinVar contains an entry for this variant (Variation ID: 1334142). 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) has been performed at Invitae 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. This variant disrupts the p.Arg229 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9032114, 25414397, 31754975; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.