Submissions for variant NM_000545.8(HNF1A):c.369GCA[4] (p.Gln125dup)

dbSNP: rs193922596

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222007	SCV002499560	likely pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.375_377dup variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 125 (p.Gln125dup) within exon 2 of NM_000545.8. The c.375_377dup variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is also 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). Additionally, 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, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 8 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). In summary, c.375_377dup 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 9/30/2021): PM4_Supporting, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP1_Strong.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030501	SCV000053172	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	RCV001852603	SCV002180433	uncertain significance	not provided	2022-02-17	criteria provided, single submitter	clinical testing	This variant, c.375_377dup, results in the insertion of 1 amino acid(s) of the HNF1A protein (p.Gln125dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 23348805; Invitae). ClinVar contains an entry for this variant (Variation ID: 36820). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319430	SCV002604955	uncertain significance	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 rs193922596 with MODY3.