Submissions for variant NM_000545.8(HNF1A):c.1340C>T (p.Pro447Leu)

gnomAD frequency: 0.00001  dbSNP: rs137853236

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810399	SCV002059989	pathogenic	Monogenic diabetes	2021-12-31	reviewed by expert panel	curation	The c.1340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 447 (p.(Pro447Leu)) of NM_000545.8. This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY ([MODY probability calculator result <50%/HNF4A not tested) (PS2_Supporting; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro447Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMIDs: 27899486, 12530534, 10585442, 32910913, 32910913). This variant was identified in 11 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 15 informative meioses in families with MODY (PP1_Strong; internal lab contributors), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.1340C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PS4, PP1_Strong, PP3, PP4, PS2_Supporting, PM2_Supporting, PS3_Moderate.
Athena Diagnostics	RCV000713784	SCV000844416	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed reduction in transcription activity (PMID: 24915262, 10585442, 12530534).
Fulgent Genetics, Fulgent Genetics	RCV000762891	SCV000893281	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	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526899	SCV001737645	pathogenic	Maturity onset diabetes mellitus in young	2021-05-26	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1340C>T (p.Pro447Leu) results in a non-conservative amino acid change located in the C-terminal domain (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 1.2e-05 in 249186 control chromosomes (gnomAD). c.1340C>T has been reported in the literature in multiple individuals affected with or suspected of Maturity Onset Diabetes of the Young 3 (example: Yamagata_1996, Estalella_2007. Yorifuji_2018) . These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant was found to have reduced DNA binding and transcriptional activity (example: Thomas_2002, Najmi_2017). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000713784	SCV002206017	pathogenic	not provided	2022-11-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 12530534). 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. ClinVar contains an entry for this variant (Variation ID: 14928). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the HNF1A protein (p.Pro447Leu).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001526899	SCV002605475	pathogenic	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 rs137853236 with MODY3.
GeneDx	RCV000713784	SCV002770333	pathogenic	not provided	2023-10-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of trans-activation activity and dominant negative effect (Vaxillaire et al., 1999; Najmi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20393147, 16496320, 11058894, 24915262, 29207974, 34496959, 12530534, 26646800, 30121369, 12574234, 28701371, 21224407, 17937063, 17573900, 29927023, 18838325, 11296231, 8945470, 9075819, 32041611, 10585442, 27899486, 36227502)
OMIM	RCV000016065	SCV000036333	pathogenic	Maturity-onset diabetes of the young type 3	1997-04-01	no assertion criteria provided	literature only