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

dbSNP: rs1364708195

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003446924	SCV004174142	pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	The c.526+1G>C 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 (PM2_Supporting). This variant was identified in nine 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% and negative genetic testing for HNF4A) (PP4, internal lab contributor). This variant segregated with diabetes, with three informative meioses in three families (PP1_Moderate, internal lab collaborators). The HNF1A(NM_000545.8):c.526+1G>A variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>C has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33 bp 64% vs. 65%). In summary, c.526+1G>C 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, PS4, PP1_Moderate, PS1_Supporting, PP4, PM2_Supporting.
Genetic Services Laboratory, University of Chicago	RCV001817817	SCV002069261	pathogenic	not provided	2018-10-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HNF1A gene demonstrated a sequence change in the canonical splice donor site site of intron 2, c.526+1G>C. This pathogenic sequence change has previously been described in a patients with HNF1A-related disorders (PMID: 18003757). This pathogenic sequence change is predicted to affect normal splicing of the HNF1A mRNA and result in a truncated protein. " DNA sequence analysis of the HNF1A gene demonstrated a sequence change in the canonical splice donor site site of intron 2, c.526+1G>C. This pathogenic sequence change has previously been described in a patients with HNF1A-related disorders (PMID: 18003757). This pathogenic sequence change is predicted to affect normal splicing of the HNF1A mRNA and result in a truncated protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001817817	SCV004295429	pathogenic	not provided	2023-12-13	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: 18003757, 31754975, 33477506). ClinVar contains an entry for this variant (Variation ID: 1338446). 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.