Submissions for variant NM_000545.8(HNF1A):c.962G>A (p.Arg321His)

gnomAD frequency: 0.00004  dbSNP: rs751761766

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248940	SCV001422719	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Arg321His variant in HNF1A has not been previously reported in individuals with MODY, but has been identified in 0.005% (1/19946) of East Asian chromosomes, 0.0032% (1/30616) of South Asian chromosomes, and 0.0015% (2/129116) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751761766). 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.Arg321His variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319683	SCV002604895	likely risk allele	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 rs751761766 with MODY3.
Fulgent Genetics, Fulgent Genetics	RCV002480859	SCV002780540	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	2022-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004769971	SCV005381042	uncertain significance	not specified	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.962G>A (p.Arg321His) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 1613928 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 (2.2e-05 vs 2.5e-05), allowing no conclusion about variant significance. c.962G>A has been reported in the literature in an individual suspected with Maturity Onset Diabetes Of The Young 3 (Zhang_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15387959). ClinVar contains an entry for this variant (Variation ID: 972763). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005094177	SCV005820068	uncertain significance	not provided	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 321 of the HNF1A protein (p.Arg321His). This variant is present in population databases (rs751761766, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of HNF1A-related conditions (PMID: 15387959, 31264968). ClinVar contains an entry for this variant (Variation ID: 972763). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. 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.