Submissions for variant NM_000545.8(HNF1A):c.731G>T (p.Arg244Ile)

dbSNP: rs193922602

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222011	SCV002499530	uncertain significance	Monogenic diabetes	2022-04-12	reviewed by expert panel	curation	The c.731G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to isoleucine at codon 244 (p.Arg244Ile) 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 is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.939, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 21224407); therefore, PP4 cannot be applied. Another missense variant, c.732A>T (p.Arg244Ser) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 cannot be applied. In summary, c.731G>T 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 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030509	SCV000053180	likely pathogenic	Maturity-onset diabetes of the young type 3	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852604	SCV002214286	uncertain significance	not provided	2021-04-17	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with isoleucine at codon 244 of the HNF1A protein (p.Arg244Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant has been observed in individual(s) with non-insulin-dependent diabetes mellitus (PMID: 21224407). ClinVar contains an entry for this variant (Variation ID: 36828). 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. 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463620	SCV002605014	likely pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs193922602 with MODY3.