Submissions for variant NM_000545.8(HNF1A):c.347C>T (p.Ala116Val)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004572114	SCV005050195	pathogenic	Monogenic diabetes	2024-06-09	reviewed by expert panel	curation	The c.347C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 116 (p.(Ala116Val)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than 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 as the transactivation values were not consistently within or outside the cutoffs for PS3_Moderate or BS3_Supporting (PMID: 32910913). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the East Asian subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in at least 20 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 36257325, 31658956, 12453976, internal lab contributors). At least 4 of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies or SU-sensitivity) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 24 informative meioses in multiple families (PP1_Strong; PMID: 12453976, internal lab contributors). In summary, c.347C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PP1_Strong, PS4, PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting.
Geisinger Clinic, Geisinger Health System	RCV002285549	SCV002562133	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PM2, PP1_Strong, PS4, PM5_Supporting, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560915	SCV004295424	pathogenic	not provided	2024-04-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 116 of the HNF1A protein (p.Ala116Val). This variant is present in population databases (rs752886203, gnomAD 0.006%). This missense change has been observed in individuals with early onset diabetes and/or maturity-onset diabetes of the young (MODY) (PMID: 11315828, 12453976, 31658956, 33046911, 34746319, 36257325; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1700671). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 32910913). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002285549	SCV005399938	pathogenic	Maturity-onset diabetes of the young type 3	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5 - Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from an alanine to a valine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a minor amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (HNF1 N terminal domain; PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a threonine has been shown to cause MODY (PMID: 18003757). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with MODY (PMID: 12882939, 16917892, 27059371, 31658956). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign