Submissions for variant NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)

dbSNP: rs769086289

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810449	SCV002059974	pathogenic	Monogenic diabetes	2021-12-30	reviewed by expert panel	curation	The c.685C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 229 (p.(Arg229Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 34 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29666556, 23517481, 25411618, internal lab contributors). This variant segregated with diabetes, with at least 13 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). In summary, c.685C>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): PVS1, PM2_Supporting, PS4, PP1_Strong
GeneDx	RCV000483162	SCV000568551	pathogenic	not provided	2017-03-13	criteria provided, single submitter	clinical testing	The R229X variant in the HNF1A gene has been reported previously in association with MODY (Kaisaki et al., 1997). This variant has also been reported in an individual with liver adenomatosis and a family history of diabetes (Bacq et al., 2003). The R229X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R229X as a pathogenic variant.
Invitae	RCV000483162	SCV002243185	pathogenic	not provided	2023-09-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg229*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). This variant is present in population databases (rs769086289, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9032114, 29666556). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420064). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000483162	SCV002497640	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Geisinger Clinic, Geisinger Health System	RCV002285337	SCV002562143	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PVS1, PM2, PS4, PP1_Strong, PP4
Fulgent Genetics, Fulgent Genetics	RCV002506168	SCV002808699	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	2022-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298551	SCV004007060	pathogenic	Maturity onset diabetes mellitus in young	2023-05-05	criteria provided, single submitter	clinical testing	The p.R229* pathogenic mutation (also known as c.685C>T), located in coding exon 3 of the HNF1A gene, results from a C to T substitution at nucleotide position 685. This changes the amino acid from an arginine to a stop codon within coding exon 3. This mutation has been reported in several individuals and families with maturity-onset diabetes of the young (Kaisaki PJ et al. Diabetes, 1997 Mar;46:528-35; Ohki T et al. J Diabetes Investig, 2014 Sep;5:513-6; Goodrich JK et al. Nat Commun, 2021 Jun;12:3505; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). Other families have presented with no evidence of glucose dysfunction, but with only hepatocellular adenomas (Barbier L et al. J Hepatol, 2019 Dec;71:1184-1192; Bacq Y et al. Gastroenterology, 2003 Nov;125:1470-5). In one family, the proband presented with diabetes and the mother had multiple liver adenomas without diabetes (Globa E et al. J Pediatr Endocrinol Metab, 2017 Oct;30:1095-1103). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003298551	SCV004038405	pathogenic	Maturity onset diabetes mellitus in young	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.685C>T (p.Arg229X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251144 control chromosomes. c.685C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (example, Furuzawa_2008). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9032114, 10078571, 10333057, 16602010, 14598263, 12355088, 17407387, 18672310). Eight submitters including the ClinGen Monogenic Diabetes Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV000483162	SCV004229331	pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families.
Genetic Services Laboratory, University of Chicago	RCV000483162	SCV003839581	pathogenic	not provided	2022-09-29	no assertion criteria provided	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.685C>T, which results in the creation of a premature stop codon at amino acid position 229, . p.Arg229*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HNF1A protein with potentially abnormal function. This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.00080% (dbSNP rs769086289). This sequence change has previously been described in multiple individuals with HNF1A-related diabetes (PMID: 29666556, 23517481, 25411618, 28862987, 9032114). Based on these evidences, this sequence change is classified as pathogenic.