Submissions for variant NM_000545.8(HNF1A):c.1513C>A (p.His505Asn)

gnomAD frequency: 0.00001  dbSNP: rs577078110

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001794557	SCV002032357	uncertain significance	Monogenic diabetes	2021-12-09	reviewed by expert panel	curation	The c.1513C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to asparagine at codon 505 (p.(His505Asn)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.7549, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 27899486). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of .00009515, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). This variant was identified in at least 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 31595705, PMID 29207974, internal lab contributor). One of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID 31595705). Additionally, the variant segregated with diabetes, with 4 informative meioses in 2 families with MODY (PP1_Strong; PMID 3159570, internal lab contributor). This variant has also been identified in multiple normoglycemic individuals, however they are under age 70 and therefore BS2 cannot be applied (PMID: 27899486, internal lab contributor). In summary, the c.1513C>A variant 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): BS1, PP1_Strong, PP3, PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034640	SCV002108593	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 505 of the HNF1A protein (p.His505Asn). This variant is present in population databases (rs577078110, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young, diabetes mellitus, and/or unaffected individuals (PMID: 18003757, 24097065, 29207974). ClinVar contains an entry for this variant (Variation ID: 1327613). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 27899486). 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.
Mendelics	RCV002246508	SCV002517182	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482315	SCV002800139	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	2022-03-17	criteria provided, single submitter	clinical testing