Submissions for variant NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)

dbSNP: rs1057520291

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222032	SCV002499509	pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 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). This variant segregated with diabetes, with 13 informative meioses in 5 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 9097962, 10102714, 12530534, 12574234, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.511C>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 September 30, 2021): PVS1, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate.
GeneDx	RCV000436030	SCV000513245	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced DNA binding ability, transactivation potential and impaired mRNA stability (Thomas et al., 2002); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29439679, 9097962, 12574234, 27420379, 26641800, 12530534)
Athena Diagnostics	RCV000436030	SCV000613619	pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (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 show that this variant results in reduced transactivation activity as well as loss of DNA binding activity (PMID: 10585442, 12107757, 12530534, 12574234). The variant is located in a region that is considered important for protein function and/or structure.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000436030	SCV002241489	pathogenic	not provided	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg171*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young 3 (PMID: 9097962). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this HNF1A variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 34,079 individuals referred to our laboratory for HNF1A testing. ClinVar contains an entry for this variant (Variation ID: 377965). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002338986	SCV002642221	pathogenic	Maturity onset diabetes mellitus in young	2017-02-21	criteria provided, single submitter	clinical testing	The p.R171* pathogenic mutation (also known as c.511C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at nucleotide position 511. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been observed to co-segregate with disease in families with maturity-onset diabetes of the young (MODY) (Vaxillaire M et al, Hum. Mol. Genet. 1997; 6(4):583-6; Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31) and has been reported in multiple proband's with a MODY phenotype (Bennett JT et al. Mol. Genet. Metab., 2015 Mar;114:451-8; de Santana LS et al. Clin. Genet., 2017 Feb; [Epub ahead of print]). Functional studies demonstrated that this mutation significantly decreases transcriptional activity and results in the absence of DNA binding ability (Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31). 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.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004719817	SCV005326323	pathogenic	Maturity-onset diabetes of the young type 3		criteria provided, single submitter	clinical testing	The p.Arg171* variant leads to a premature termination codon and is predicted to cause loss-of-function due to a truncated or absent gene product. Functional studies have shown that the p.Arg171* variant results in loss of DNA binding ability and transactivation potential, as well as impaired mRNA stability (PMID: 12530534). This variant has been reported in several unrelated individuals with HNF1A-related MODY (PMID: 9097962, 27420379, 26641800, 35472491, 29439679). The p.Arg171* variant is absent from large population studies (gnomAD v2.1.1).
PreventionGenetics, part of Exact Sciences	RCV004752888	SCV005361597	pathogenic	HNF1A-related disorder	2024-05-23	no assertion criteria provided	clinical testing	The HNF1A c.511C>T variant is predicted to result in premature protein termination (p.Arg171*). This variant has been reported to be pathogenic in multiple individuals with Maturity Onset Diabetes of the Young (MODY) (Vaxillaire et al 1997. PubMed ID: 9097962; Thomas H et al 2002. PubMed ID: 12530534; Mohan V et al 2018. PubMed ID: 29439679). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been classified as pathogenic by ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/377965/). This variant is interpreted as pathogenic.