Submissions for variant NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)

dbSNP: rs754728827

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222031	SCV002499510	pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.526C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 176 (p.(Gln176Ter)) 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 also was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 18003757, internal lab contributors). This variant has a minor allele frequency of 0.000008856 in the gnomAD v2.1.1 European non-Finnish population and zero copies in other subpopulations, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant segregated with diabetes, with 5 informative meioses in 4 families with MODY (PP1_Strong; 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.526C>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 9/30/2021): PVS1, PS4, PM2_Supporting, PP1_Strong, PP4_Moderate.
GeneDx	RCV000414498	SCV000490557	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16496320, 25525159, 29625052, 36208030, 36451132, 35472491, 32238361, 34440499, 36257325, 36793123, 31166087, 12107757)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249012	SCV001422862	pathogenic	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young type 3 (MODY3) and has been identified in 0.0008856% (1/112922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754728827). This variant has also been reported in ClinVar (VariationID: 372380) as pathogenic by GeneDx. In vitro functional studies in HeLa cells transfected with the variant demonstrating null expression and transactivation activities similar to those of an empty vector alone provide some evidence that the p.Gln176Ter variant may impact protein function (PMID: 12107757). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 576, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY3. In summary, this variant meets criteria to be classified as pathogenic for MODY3 in an autosomal dominant manner based on the prediction that it will cause loss of function of the HNF1A gene, low frequency of the variant in the general population, and in vitro functional studies. ACMG/AMP Criteria applied: PVS1, PM2, PS3_moderate (Richards 2015).
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001526667	SCV001656074	pathogenic	Maturity onset diabetes mellitus in young	2018-04-23	criteria provided, single submitter	clinical testing	The c.526C>T (p.Gln176*, rs754728827) variant is located in exon 2 of the HNF1A gene. This single nucleotide substitution creates a premature stop codon at amino acid position 176. This variant has been reported in an individual with a clinical diagnosis of MODY (PMID: 12107757), and variants that cause a loss of protein function are a well described cause of MODY. This is not a common variant in the general population (1 out of 245246 alleles in GnomAD). In summary, this variant is interpreted to be pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000414498	SCV002067313	pathogenic	not provided	2019-04-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.526C>T, which results in the creation of a premature stop codon at amino acid position 176, p.Gln176*. This pathogenic 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 pathogenic sequence change has previously been described in a patient with MODY (PMID: 12107757).
Geisinger Clinic, Geisinger Health System	RCV001249012	SCV002562136	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PVS1, PM2, PS4, PP1_Supporting, PP4_Moderate
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001526667	SCV002605472	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 rs754728827 with MODY3.
Ambry Genetics	RCV001526667	SCV002645179	pathogenic	Maturity onset diabetes mellitus in young	2021-11-18	criteria provided, single submitter	clinical testing	The c.526C>T (p.Q176*) alteration, located in exon 2 (coding exon 2) of the HNF1A gene, consists of a C to T substitution at nucleotide position 526. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 176. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was described in multiple families with suspected MODY (Xu, 2002; Gaál, 2021). Functional studies showed this alteration resulted in a significant decrease in transactivation compared to wild-type (Xu, 2002). Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV001249012	SCV002762713	pathogenic	Maturity-onset diabetes of the young type 3	2022-03-23	criteria provided, single submitter	clinical testing	The HNF1A c.526C>T (p.Gln176Ter) nonsense variant results in the substitution of glutamine at amino acid position 176 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in at least six individuals with maturity onset diabetes of the young (Xu et al. 2002; Ma et al. 2020; Gaál et al. 2021). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). In vitro studies in HeLa cells transfected with the c.526C>T variant demonstrated that the c.526C>T variant resulted in null expression and no detectable protein. Transactivation studies using a luciferase reporter assay showed 24.16% activity compared to wildtype, which was similar to an empty vector alone (Xu et al. 2002). Based on the available evidence, the c.526C>T (p.Gln176Ter) variant is classified as pathogenic for maturity onset diabetes of the young.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414498	SCV003442109	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 372380). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 12107757). This variant is present in population databases (rs754728827, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln176*) 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). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000414498	SCV004229330	pathogenic	not provided	2022-09-29	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 has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 12107757.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001526667	SCV004848499	pathogenic	Maturity onset diabetes mellitus in young	2020-11-06	criteria provided, single submitter	clinical testing	The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young (MODY; Xu 2002 PMID: 12107757) and has been identified in 0.0009% (1/112922) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (VariationID: 372380). In vitro functional studies provide some evidence that the p.Gln176Ter variant may impact protein function (Xu 2002 PMID: 12107757). This nonsense variant leads to a premature termination codon at position 176, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY. In summary, this variant meets criteria to be classified as pathogenic for MODY in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS3_Supporting.