Submissions for variant NM_000545.8(HNF1A):c.1136C>A (p.Pro379His)

dbSNP: rs371717826

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003481231	SCV004223880	benign	Monogenic diabetes	2023-12-10	reviewed by expert panel	curation	The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of proline to histidine at codon 379 (p.(Pro379His)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001567, which is greater than the MDEP threshold for BA1 (0.0001)(BA1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Pro379His protein has transcriptional activity on insulin promoter 62% of WT in RINm5f cells and 78% of WT in HeLA cells (PMID 15883474). While one cell line is greater than the MDEP BS3 cutoff of 75%, one is between the ClinGen MDEP cutoffs for PS3 (<=40%) and BS3, and therefore neither PS3 nor BS3 is applied. This variant was identified in one family and segregated with diabetes with two informative meioses; however, this does not meet the thresholds for PP1 or PS4 set by the ClinGen MDEP (PMIDs: 27236918, 15883474). An individual in this family had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID 15883474). Another missense variant, c.1136C>G (p.Pro379Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379His (PM5_Supporting). In summary, c.1136C>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BA1, PM5_Supporting, PP4_Moderate, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001966930	SCV002248325	likely pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 379 of the HNF1A protein (p.Pro379His). This variant is present in population databases (rs371717826, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 15883474, 25555642, 26059258, 30455330, 31264968; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1471754). 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 not 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: 15883474). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282671	SCV002572324	uncertain significance	not specified	2023-09-08	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1136C>A (p.Pro379His) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Other variant affecting the same amino acid residue (Pro379) have been reported in association with Maturity Onset Diabetes Of The Young 3 in the HGMD database and with limiting/conflicting reports of pathogenicity in the ClinVar database. This supports a possible functional relevance of this residue towards protein function. 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 5.2e-05 in 250114 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. c.1136C>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 3 (e.g. Dominguez-Lopez_2005, Bennet_2015, Chambers_2016, Juszczak_2019, Yu_2019) and was demonstrated to segregate with disease across three generations in at-least one Mexican family (Dominguez-Lopez_2005). These data indicate that the variant is likely to be associated with disease although the ethnicity of the reported individuals was not specified across all ascertained reports cited here. At least one publication reports experimental evidence evaluating an impact on protein function. When assayed with the human insulin promotor, the variant was found to retain approximately 60% transactivational activity when compared to wild-type (Dominguez-Lopez_2005). The following publications have been ascertained in the context of this evaluation (PMID: 25555642, 26059258, 15883474, 30455330, 31264968). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. At-least one submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002479623	SCV002779636	likely pathogenic	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	2022-04-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004753455	SCV005341640	uncertain significance	HNF1A-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The HNF1A c.1136C>A variant is predicted to result in the amino acid substitution p.Pro379His. This variant has been reported in individuals with maturity-onset diabetes of the young (MODY, Bennett et al. 2015. PubMed ID: 25555642; Table S8, Kingsmore et al. 2022. PubMed ID: 36007526). Additionally, it was identified in multiple members a family with diabetes, and was reported to segregate with disease (Domínguez-López et al. 2005. PubMed ID: 15883474). In vitro functional studies using RINm5f and HeLa cells have demonstrated that expression of this variant resulted in a mildly reduced transactivation of the human insulin promoter to ~ 62% and 78% of wild-type, respectively (Domínguez-López et al. 2005. PubMed ID: 15883474). Several different missense changes impacting the same amino acid (p.Pro379Ala, p.Pro379Ser, p.Pro379Thr, p.Pro379Arg) have also been reported in MODY patients but the classification of those variants range from benign to pathogenic in ClinVar (Bellanne-Chantelot. 2008. PubMed ID: 18003757; Xu et al. 2005. PubMed ID: 15657605; https://www.ncbi.nlm.nih.gov/clinvar/variation/4319; https://www.ncbi.nlm.nih.gov/clinvar/variation/972818/; https://www.ncbi.nlm.nih.gov/clinvar/variation/1675516/ ). This variant is reported in 0.029% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as benign by the ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/1471754/). At PreventionGenetics, this variant was reported in the homozygous state in a healthy parent of an individual with MODY, who also harbored a frameshift variant in GCK, thus providing evidence against pathogenicity (internal data). Taken together, although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.