Submissions for variant NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)

dbSNP: rs765432081

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810450	SCV002059982	pathogenic	Monogenic diabetes	2021-12-22	reviewed by expert panel	curation	The c.475C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 159 (p.(Arg159Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in multiple individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.476G>A, p.(Arg159Gln), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg159Trp has an equal or greater Grantham distance. (PM5). This variant was identified in thirteen unrelated families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; [internal lab contributors; Exeter, BMRC, Paris]). Lastly, this variant segregated with diabetes, with eight informative meioses in five families with MODY (PP1_Strong; [internal lab contributors; Exeter]). In summary, c.475C>T meets the criteria to be classified as pathogneic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5, PS4, PP1_Strong.
GeneDx	RCV000494442	SCV000582396	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9754819, 12453420, 28410371, 28012402, 11058894, 30191644, 31264968, 33538814, 18003757, 34440499, 34556497, 9075818, 9097962, 23548576)
Genetics and Molecular Pathology, SA Pathology	RCV002272261	SCV002556597	likely pathogenic	Maturity-onset diabetes of the young type 3	2021-07-08	criteria provided, single submitter	clinical testing
Geisinger Clinic, Geisinger Health System	RCV002272261	SCV002562135	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PP3, PP4, PM1_Supporting, PM2, PM5, PS4, PP1_Strong
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464213	SCV002605468	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 rs765432081 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494442	SCV003442075	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg159 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9097962). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429750). This missense change has been observed in individuals with diabetes (PMID: 9075818, 9754819, 12050210, 18672310, 27083284, 30191644). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the HNF1A protein (p.Arg159Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002464213	SCV003800817	pathogenic	Maturity onset diabetes mellitus in young	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal domain (IPR006899) 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 4e-06 in 251546 control chromosomes. c.475C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (example, PMID: 12050210, 9754819, 9075818, 9313764, 10333057, 18672310, 17937063, 19150152). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and the ClinGen Monogenic Diabetes Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV001175312	SCV001250628	likely pathogenic	Diabetes mellitus	2020-04-28	no assertion criteria provided	research	PS1 PM2 PP3
deCODE genetics, Amgen	RCV002272261	SCV004022263	likely pathogenic	Maturity-onset diabetes of the young type 3	2023-07-21	no assertion criteria provided	research	The variant NM_000545.8:c.475C>T (chr12:120988981) in HNF1A was detected in 6 heterozygotes out of 58K WGS Icelanders (MAF= 0,005%). Following imputation in a set of 166K Icelanders (12 imputed heterozygotes) we observed an association with diabetes mellitus using 3676 cases and 332804 controls (OR= 14.65, P= 5.32e-03) and non-insulin dependent diabetes mellitus using 5864 cases and 298172 controls (OR= 10.82, P= 1.59e-02). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PP3, PP5) this variant classifies as likely pathogenic.