Submissions for variant NM_000545.8(HNF1A):c.526+1G>A

dbSNP: rs1364708195

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003446599	SCV004174141	pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	The c.526+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading 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. This variant was identified in 12 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 21242637, internal lab contributors), including an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate, internal lab contributor). This variant segregated with diabetes, with six informative meioses in five families with MODY (PP1_Strong, internal lab collaborators). In summary, c.526+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049923	SCV001214002	pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the HNF1A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with maturity-onset diabetes of the young (PMID: 11272211, 21242637, 31754975). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 846588). 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.
Genetic Services Laboratory, University of Chicago	RCV001049923	SCV002067336	pathogenic	not provided	2019-06-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change in the canonical splice donor site of intron 2, c.526+1G>A. This sequence change is absent from large population databases such as ExAC and gnomAD. This pathogenic sequence change has been previously described in three affected individuals from a family with maturity-onset diabetes of the young type 3 (MODY3) (PMID: 11272211). This pathogenic sequence change is predicted to affect normal splicing of the HNF1A gene, leading to an abnormal protein, which may be degraded, or may lead to production of a truncated HNF1A protein with potentially abnormal function. " DNA sequence analysis of the HNF1A gene demonstrated a sequence change in the canonical splice donor site of intron 2, c.526+1G>A. This sequence change is absent from large population databases such as ExAC and gnomAD. This pathogenic sequence change has been previously described in three affected individuals from a family with maturity-onset diabetes of the young type 3 (MODY3) (PMID: 11272211). This pathogenic sequence change is predicted to affect normal splicing of the HNF1A gene, leading to an abnormal protein, which may be degraded, or may lead to production of a truncated HNF1A protein with potentially abnormal function.
GeneDx	RCV001049923	SCV002504369	pathogenic	not provided	2024-03-02	criteria provided, single submitter	clinical testing	Identified in individuals with early onset diabetes in published literature (PMID: 11272211, 20393147); Canonical splice site variant predicted to result in a null allele 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: 21242637, 25525159, 31754975, 20393147, 32238361, 16496320, 36257325, 11272211)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490031	SCV004241457	pathogenic	Maturity onset diabetes mellitus in young	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.526+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.526+1G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Frayling_2001, Pearson_2007, Fu_2020) with evidence of cosegregation with disease. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11272211, 17407387, 31754975). Four submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.