Submissions for variant NM_000545.8(HNF1A):c.1502-6G>A

dbSNP: rs1458430820

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248994	SCV001422838	pathogenic	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The c.1502-6G>A variant in HNF1A has been reported in 31 individuals with maturity-onset diabetes of the young, segregated with disease in 13 affected relatives from 4 families (PMID: 16249556, 12378390, 26479152, 12107757, 21683639, 18003757, 18838325, 20210571, 23348805), and has been identified in 0.0009% (1/113114) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1458430820). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The c.1502-6G>A variant affects a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (Sujjitjoon et al, 2008. In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease, more affected individuals with the variant than expected, and absence of the variant from the general population. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PM1_Supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002241648	SCV002511552	pathogenic	Maturity onset diabetes mellitus in young	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1502-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 3' acceptor site. Four predict the variant creates a 3' acceptor site. Splicing studies using cells expressing the variant confirmed the impact on splicing, where the variant resulted in the skipping of exon 7 and a premature termination codon (Bulman_2002). The variant allele was found at a frequency of 4e-06 in 250674 control chromosomes. c.1502-6G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 and was reported to segregate in several affected families (Bulman_2002, Xu_2002, Malecki_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003153959	SCV003842428	likely pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 20210571, 23348805, 12378390, 12107757, 18003757, 26479152, 18838325, 16249556, 21683639, 35081418)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003153959	SCV004295437	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	This variant has been observed in individuals with maturity-onset diabetes of the young (MODY) (PMID: 16249556, 21683639, 26479152, 35081418). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change falls in intron 7 of the HNF1A gene. It does not directly change the encoded amino acid sequence of the HNF1A protein. This variant is also known as IVS7-6G>A. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 35081418). Experimental studies have shown that this variant affects HNF1A function (PMID: 35081418). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 972783).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002241648	SCV004848483	pathogenic	Maturity onset diabetes mellitus in young	2020-11-06	criteria provided, single submitter	clinical testing	The c.1502-6G>A variant in HNF1A has been reported in at least 6 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 10 affected relatives from 4 families (Malecki 2005 PMID: 16249556, Bulman 2002 PMID: 12378390, Bacon 2016 PMID: 26479152, Xu 2002 PMID: 12107757, Kyithar 2011 PMID: 21683639, Ellard 2013 PMID: 23771172, Skupien 2008 PMID: 18838325, Katra 2010 PMID: 20210571) and has been identified in 0.001% (1/113114) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 3' splice region. Computational tools predict a splicing impact with creation of a new acceptor site, though this information is not predictive enough to determine pathogenicity. Functional studies in patient's lymphoblastoid cell lines provide some evidence that this variant causes skipping of exon 7 and use of the new acceptor site in intron 7, ultimately predicting a frameshift with a premature termination codon at position 485 (Bulman 2002 PMID: 12378390). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP1_Strong, PP3, PS3_Supporting.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002241648	SCV002604945	uncertain risk allele	Maturity onset diabetes mellitus in young		flagged submission	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 rs1458430820 with MODY3.