Submissions for variant NM_000545.8(HNF1A):c.527-1G>A

dbSNP: rs1555211904

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002222045	SCV002499511	pathogenic	Monogenic diabetes	2022-04-10	reviewed by expert panel	curation	The c.527-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 2 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10588527, internal lab contributors). Additionally, this variant was identified in at least 2 individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), including one considered highly specific based on sulfonylurea-responsiveness (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 10588527, internal lab contributors). In summary, c.527-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong.
GeneDx	RCV000521422	SCV000616742	pathogenic	not provided	2022-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11315828, 10588527)
Athena Diagnostics	RCV000521422	SCV000844426	pathogenic	not provided	2020-11-11	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family, however, the available information does not rule out an apparent association due to chance. Computational tools yielded predictions that this variant may interfere with normal RNA splicing.
Geisinger Clinic, Geisinger Health System	RCV002285352	SCV002562137	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PVS1, PM2, PP3, PP4, PS4_Moderate, PP1_Strong
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319520	SCV002604973	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 rs1555211904 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521422	SCV003442015	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor 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 individual(s) with HNF1A-related conditions (PMID: 10588527). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2nt-1G>A. ClinVar contains an entry for this variant (Variation ID: 449035). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002319520	SCV004241605	pathogenic	Maturity onset diabetes mellitus in young	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.527-1G>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 3' splice acceptor site, and two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251006 control chromosomes (gnomAD). c.527-1G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 with evidence of cosegregation with disease (Ng_1999, Mirshahi_2022). 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: 10588527, 36257325). Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.