Submissions for variant NM_000545.8(HNF1A):c.139G>C (p.Gly47Arg)

gnomAD frequency: 0.00003  dbSNP: rs373180062

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222060	SCV002499559	uncertain significance	Monogenic diabetes	2022-04-02	reviewed by expert panel	curation	The c.139G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 47 (p.(Gly47Arg)) of NM_000545.8. This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; (PMID: 23274891, internal lab contributors). The calculated MODY probability was <50% for each of these 4 individuals; therefore PP4 could not be applied. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Gly47Arg protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 32910913). Another missense variant, c.140G>A (p.(Gly47Glu)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.139G>C 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 9/30/21): PS4_Moderate, PM2_Supporting, BS3_Supporting.
Illumina Laboratory Services, Illumina	RCV001112158	SCV001269785	uncertain significance	Maturity-onset diabetes of the young type 3	2018-01-24	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001112158	SCV001422729	uncertain significance	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Gly47Arg variant in HNF1A has not been previously reported in individuals with maturity-onset diabetes of the young and has been identified in 0.004% (1/24066) of African chromosomes and 0.0008% (1/123988) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373180062). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Glycine (Gly) at position 47 is not highly conserved in mammals and evolutionary distant species, and 3 species (opossum, wallaby, and Tasmanian devil) carry a Arginine (Arg), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.Gly47Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464389	SCV002605553	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. Sufficient evidence is found to confer the association of this particular variant rs373180062 with MODY3.
Fulgent Genetics, Fulgent Genetics	RCV002482205	SCV002780928	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	2022-05-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004693683	SCV005192019	uncertain significance	not provided		criteria provided, single submitter	not provided
Labcorp Genetics (formerly Invitae), Labcorp	RCV004693683	SCV005823658	uncertain significance	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the HNF1A protein (p.Gly47Arg). This variant is present in population databases (rs373180062, gnomAD 0.004%). This missense change has been observed in individual(s) with HNF1A-related conditions (PMID: 23274891, 23348805, 32741144, 32910913). ClinVar contains an entry for this variant (Variation ID: 882461). 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%. Experimental studies have shown that this missense change does not substantially affect HNF1A function (PMID: 32910913). 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.