Submissions for variant NM_000545.8(HNF1A):c.864delinsCC (p.Gly292fs)

dbSNP: rs1593058932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008770	SCV001168559	pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing	Frameshift 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; This variant is associated with the following publications: (PMID: 24355479, 33565752, 31936598, 30755392)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319613	SCV002604894	likely 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. However, more evidence is required to confer the association of this particular variant rs1593058932 with MODY3.
Ambry Genetics	RCV002319613	SCV002687813	pathogenic	Maturity onset diabetes mellitus in young	2023-12-27	criteria provided, single submitter	clinical testing	The c.864delGinsCC pathogenic mutation, located in coding exon 4 of the HNF1A gene, results from the deletion of one nucleotide and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.G292Rfs*25). This mutation has been reported in individuals with a clinical diagnosis of maturity-onset diabetes of the young (Wheeler BJ et al. J Diabetes Metab Disord, 2013 Dec;12:46; Yalçntepe S et al. J Clin Res Pediatr Endocrinol, 2021 Aug;13:320-331). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001008770	SCV004563202	pathogenic	not provided	2023-09-30	criteria provided, single submitter	clinical testing	The HNF1A c.864delinsCC; p.Gly292ArgfsTer25 variant (rs1593058932) is reported in the literature in individuals affected with MODY (Ji 2019, Wheeler 2013, Yalcintepe 2021). This variant results in the same amino acid frameshift as a different well-characterized pathogenic variant also associated with MODY, c.872dupC; p.Gly292ArgfsTer25 (Ellard 2000, Estalella 2007, Johnson 2018, Pavic 2018, Yamagata 1996). The c.864delinsCC variant is reported in ClinVar (Variation ID: 817605) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide and inserting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.864delinsCC variant is considered to be pathogenic. References: Ellard S. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mutat. 2000 Nov;16(5):377-85. PMID: 11058894. Estalella I et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf). 2007 Oct;67(4):538-46. PMID: 17573900. Ji J et al. A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2):a003756. PMID: 30755392. Johnson SR et al. Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. Pediatr Diabetes. 2018 Jun;19(4):656-662. PMID: 29417725. Pavic T et al. Maturity onset diabetes of the young due to HNF1A variants in Croatia. Biochem Med (Zagreb). 2018 Jun 15;28(2):020703. PMID: 29666556. Wheeler BJ et al. Frequency and genetic spectrum of maturity-onset diabetes of the young (MODY) in southern New Zealand. J Diabetes Metab Disord. 2013 Dec 19;12(1):46. PMID: 24355479. Yamagata K et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996 Dec 5;384(6608):455-8. PMID: 8945470. Yalcintepe S et al. The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region. J Clin Res Pediatr Endocrinol. 2021 Aug 23;13(3):320-331. PMID: 33565752.
Molecular Genetics, Royal Melbourne Hospital	RCV003994190	SCV004812865	pathogenic	Monogenic diabetes	2023-09-04	criteria provided, single submitter	clinical testing	This multi-nucleotide sequence change in HNF1A is a frameshift variant observed to cause a premature stop codon (PMID: 10585442), p.(Gly292Argfs*25), in biologically relevant exon 4/10 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 8945470, 9566924, 29792621). Also described as c.863_864insC p.(Pro289Alafs*28) when not in combination with the common synonymous variant, rs56348580. The variant has quality flags in the population database gnomAD v2.1 and v3.1 and is not a reliable source for population allele frequency evidence. The frameshift variant occurs in a mutational hotspot and accounts for ~20% of HNF1A-related maturity-onset diabetes of the young (MODY) families (PMID: 24518839). It segregates with non-insulin-dependent diabetes mellitus in multiple families and has been identified as a de novo occurrence with confirmed parental relationships in at least one individual (PMID: 9166684). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002319613	SCV005184528	pathogenic	Maturity onset diabetes mellitus in young	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.864delinsCC (p.Gly292ArgfsX25) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 259326 control chromosomes (gnomAD). c.864delinsCC has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Yalcintepe_2021). The following publication has been ascertained in the context of this evaluation (PMID: 33565752). ClinVar contains an entry for this variant (Variation ID: 817605). Based on the evidence outlined above, the variant was classified as pathogenic.